chr5-140848680-G-T

Position:

• chr5-140848680-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_031857.2(PCDHA9):​c.185G>T​(p.Arg62Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,592,250 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (2 hom., cov: 29)
  • Exomes 𝑓: 0.000042 (3 hom.)
• Consequence: PCDHA9 NM_031857.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71

Genes affected

PCDHA9 (HGNC:8675): (protocadherin alpha 9) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA2 (HGNC:8668): (protocadherin alpha 2) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA3 (HGNC:8669): (protocadherin alpha 3) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA4 (HGNC:8670): (protocadherin alpha 4) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA5 (HGNC:8671): (protocadherin alpha 5) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA6 (HGNC:8672): (protocadherin alpha 6) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA7 (HGNC:8673): (protocadherin alpha 7) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA8 (HGNC:8674): (protocadherin alpha 8) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA9	NM_031857.2	c.185G>T	p.Arg62Leu	missense_variant	1/4	ENST00000532602.2
PCDHA1	NM_018900.4	c.2394+59996G>T		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+51328G>T		intron_variant		ENST00000526136.2
PCDHA3	NM_018906.3	c.2394+45089G>T		intron_variant		ENST00000522353.3
PCDHA4	NM_018907.4	c.2385+39108G>T		intron_variant		ENST00000530339.2
PCDHA5	NM_018908.3	c.2352+24553G>T		intron_variant		ENST00000529859.2
PCDHA6	NM_018909.4	c.2394+18195G>T		intron_variant		ENST00000529310.6
PCDHA7	NM_018910.3	c.2355+11942G>T		intron_variant		ENST00000525929.2
PCDHA8	NM_018911.3	c.2394+4965G>T		intron_variant		ENST00000531613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA9	ENST00000532602.2	c.185G>T	p.Arg62Leu	missense_variant	1/4	1	NM_031857.2	P1
PCDHA1	ENST00000504120.4	c.2394+59996G>T		intron_variant		1	NM_018900.4	P1
PCDHA3	ENST00000522353.3	c.2394+45089G>T		intron_variant		1	NM_018906.3	P1
PCDHA7	ENST00000525929.2	c.2355+11942G>T		intron_variant		1	NM_018910.3	P1
PCDHA2	ENST00000526136.2	c.2388+51328G>T		intron_variant		1	NM_018905.3	P1
PCDHA6	ENST00000529310.6	c.2394+18195G>T		intron_variant		1	NM_018909.4	P1
PCDHA5	ENST00000529859.2	c.2352+24553G>T		intron_variant		1	NM_018908.3	P1
PCDHA4	ENST00000530339.2	c.2385+39108G>T		intron_variant		1	NM_018907.4	P1
PCDHA8	ENST00000531613.2	c.2394+4965G>T		intron_variant		1	NM_018911.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000667 AC: 10 AN: 149828 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000601

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000484 AC: 12 AN: 247728 Hom.: 0 AF XY: 0.0000596 AC XY: 8 AN XY: 134180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000416 AC: 60 AN: 1442422 Hom.: 3 Cov.: 89 AF XY: 0.0000474 AC XY: 34 AN XY: 717698

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000317

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000401

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.0000667 AC: 10 AN: 149828 Hom.: 2 Cov.: 29 AF XY: 0.0000957 AC XY: 7 AN XY: 73136

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000601

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000982

ExAC AF: 0.0000249 AC: 3

EpiCase AF: 0.000111

EpiControl AF: 0.0000601

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2022

The c.185G>T (p.R62L) alteration is located in exon 1 (coding exon 1) of the PCDHA9 gene. This alteration results from a G to T substitution at nucleotide position 185, causing the arginine (R) at amino acid position 62 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.95	P;P
Vest4		0.61
MutPred		0.85		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.80
ClinPred		0.90	D
GERP RS		3.7
Varity_R		0.66
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781938203; hg19: chr5-140228265;