5-140848291-G-A

Variant names:

• chr5-140848291-G-A
• rs251352
• NM_018900.4:c.2394+59607G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018900.4(PCDHA1):​c.2394+59607G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 624,962 control chromosomes in the GnomAD database, including 101,055 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (21775 hom., cov: 30)
  • Exomes 𝑓: 0.55 (79280 hom.)
• Consequence: PCDHA1 NM_018900.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.917
• Publications: 12 publications found

Genes affected

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]

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]

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]

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]

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]

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]

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]

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]

PCDHA@ (HGNC:8662):

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]

PCDHA9 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.2394+59607G>A		intron_variant	Intron 1 of 3	ENST00000504120.4	NP_061723.1
PCDHA3	NM_018906.3	c.2394+44700G>A		intron_variant	Intron 1 of 3	ENST00000522353.3	NP_061729.1
PCDHA6	NM_018909.4	c.2394+17806G>A		intron_variant	Intron 1 of 3	ENST00000529310.6	NP_061732.1
PCDHA8	NM_018911.3	c.2394+4576G>A		intron_variant	Intron 1 of 3	ENST00000531613.2	NP_061734.1
PCDHA2	NM_018905.3	c.2388+50939G>A		intron_variant	Intron 1 of 3	ENST00000526136.2	NP_061728.1
PCDHA4	NM_018907.4	c.2385+38719G>A		intron_variant	Intron 1 of 3	ENST00000530339.2	NP_061730.1
PCDHA7	NM_018910.3	c.2355+11553G>A		intron_variant	Intron 1 of 3	ENST00000525929.2	NP_061733.1
PCDHA5	NM_018908.3	c.2352+24164G>A		intron_variant	Intron 1 of 3	ENST00000529859.2	NP_061731.1
PCDHA9	NM_031857.2	c.-205G>A		upstream_gene_variant		ENST00000532602.2	NP_114063.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.2394+59607G>A		intron_variant	Intron 1 of 3	1	NM_018900.4	ENSP00000420840.3
PCDHA3	ENST00000522353.3	c.2394+44700G>A		intron_variant	Intron 1 of 3	1	NM_018906.3	ENSP00000429808.2
PCDHA6	ENST00000529310.6	c.2394+17806G>A		intron_variant	Intron 1 of 3	1	NM_018909.4	ENSP00000433378.1
PCDHA8	ENST00000531613.2	c.2394+4576G>A		intron_variant	Intron 1 of 3	1	NM_018911.3	ENSP00000434655.1
PCDHA2	ENST00000526136.2	c.2388+50939G>A		intron_variant	Intron 1 of 3	1	NM_018905.3	ENSP00000431748.1
PCDHA4	ENST00000530339.2	c.2385+38719G>A		intron_variant	Intron 1 of 3	1	NM_018907.4	ENSP00000435300.1
PCDHA7	ENST00000525929.2	c.2355+11553G>A		intron_variant	Intron 1 of 3	1	NM_018910.3	ENSP00000436426.1
PCDHA5	ENST00000529859.2	c.2352+24164G>A		intron_variant	Intron 1 of 3	1	NM_018908.3	ENSP00000436557.1
PCDHA9	ENST00000532602.2	c.-205G>A		upstream_gene_variant		1	NM_031857.2	ENSP00000436042.2

Frequencies

GnomAD3 genomes AF: 0.497 AC: 73950 AN: 148700 Hom.: 21749 Cov.: 30

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.518

GnomAD4 exome AF: 0.551 AC: 262326 AN: 476142 Hom.: 79280 Cov.: 5 AF XY: 0.555 AC XY: 138573 AN XY: 249506

African (AFR) AF: 0.336 AC: 4696 AN: 13964

American (AMR) AF: 0.515 AC: 10570 AN: 20520

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 7482 AN: 13046

East Asian (EAS) AF: 0.490 AC: 16571 AN: 33840

South Asian (SAS) AF: 0.623 AC: 25237 AN: 40498

European-Finnish (FIN) AF: 0.593 AC: 20776 AN: 35064

Middle Eastern (MID) AF: 0.554 AC: 1076 AN: 1942

European-Non Finnish (NFE) AF: 0.556 AC: 161658 AN: 290850

Other (OTH) AF: 0.540 AC: 14260 AN: 26418

GnomAD4 genome AF: 0.497 AC: 74006 AN: 148820 Hom.: 21775 Cov.: 30 AF XY: 0.500 AC XY: 36309 AN XY: 72592

African (AFR) AF: 0.343 AC: 13961 AN: 40726

American (AMR) AF: 0.540 AC: 8033 AN: 14870

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 1976 AN: 3410

East Asian (EAS) AF: 0.478 AC: 2458 AN: 5138

South Asian (SAS) AF: 0.637 AC: 2985 AN: 4684

European-Finnish (FIN) AF: 0.586 AC: 5993 AN: 10232

Middle Eastern (MID) AF: 0.521 AC: 147 AN: 282

European-Non Finnish (NFE) AF: 0.558 AC: 37148 AN: 66520

Other (OTH) AF: 0.520 AC: 1075 AN: 2066

Alfa AF: 0.486 Hom.: 1832

Asia WGS AF: 0.605 AC: 2098 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Benign	0.94
PhyloP100		0.92
PromoterAI		-0.028	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs251352; hg19: chr5-140227876;