chr5-140848781-T-G

Position:

• chr5-140848781-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_031857.2(PCDHA9):​c.286T>G​(p.Cys96Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,593,236 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (24 hom., cov: 28)
  • Exomes 𝑓: 0.0026 (365 hom.)
• Consequence: PCDHA9 NM_031857.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.83

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03342223).
• BP6: Variant 5-140848781-T-G is Benign according to our data. Variant chr5-140848781-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2655772.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA9	NM_031857.2	c.286T>G	p.Cys96Gly	missense_variant	1/4	ENST00000532602.2
PCDHA1	NM_018900.4	c.2394+60097T>G		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+51429T>G		intron_variant		ENST00000526136.2
PCDHA3	NM_018906.3	c.2394+45190T>G		intron_variant		ENST00000522353.3
PCDHA4	NM_018907.4	c.2385+39209T>G		intron_variant		ENST00000530339.2
PCDHA5	NM_018908.3	c.2352+24654T>G		intron_variant		ENST00000529859.2
PCDHA6	NM_018909.4	c.2394+18296T>G		intron_variant		ENST00000529310.6
PCDHA7	NM_018910.3	c.2355+12043T>G		intron_variant		ENST00000525929.2
PCDHA8	NM_018911.3	c.2394+5066T>G		intron_variant		ENST00000531613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA9	ENST00000532602.2	c.286T>G	p.Cys96Gly	missense_variant	1/4	1	NM_031857.2	P1
PCDHA1	ENST00000504120.4	c.2394+60097T>G		intron_variant		1	NM_018900.4	P1
PCDHA3	ENST00000522353.3	c.2394+45190T>G		intron_variant		1	NM_018906.3	P1
PCDHA7	ENST00000525929.2	c.2355+12043T>G		intron_variant		1	NM_018910.3	P1
PCDHA2	ENST00000526136.2	c.2388+51429T>G		intron_variant		1	NM_018905.3	P1
PCDHA6	ENST00000529310.6	c.2394+18296T>G		intron_variant		1	NM_018909.4	P1
PCDHA5	ENST00000529859.2	c.2352+24654T>G		intron_variant		1	NM_018908.3	P1
PCDHA4	ENST00000530339.2	c.2385+39209T>G		intron_variant		1	NM_018907.4	P1
PCDHA8	ENST00000531613.2	c.2394+5066T>G		intron_variant		1	NM_018911.3	P1

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 295 AN: 148586 Hom.: 24 Cov.: 28

Gnomad AFR AF: 0.000466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00476

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000871

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.00184 AC: 456 AN: 248088 Hom.: 48 AF XY: 0.00194 AC XY: 261 AN XY: 134282

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00490

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00261 AC: 3773 AN: 1444536 Hom.: 365 Cov.: 79 AF XY: 0.00258 AC XY: 1853 AN XY: 718826

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00555

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00297

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00198 AC: 295 AN: 148700 Hom.: 24 Cov.: 28 AF XY: 0.00174 AC XY: 126 AN XY: 72604

Gnomad4 AFR AF: 0.000464

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.00476

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000871

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00194

Alfa AF: 0.00236 Hom.: 3

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00211 AC: 18

ExAC AF: 0.00159 AC: 192

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

PCDHA9: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.033	T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Pathogenic	-12	D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.86
MVP		0.87
ClinPred		0.16	T
GERP RS		3.9
Varity_R		0.96
gMVP		0.68

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: rs146253628; hg19: chr5-140228366;