NM_001384140.1:c.4801G>A

Variant names:

• chr10-53807001-C-T
• rs181306086
• NM_001384140.1:c.4801G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001384140.1(PCDH15):​c.4801G>A​(p.Gly1601Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000243 in 1,613,482 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1601G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.77
• Publications: 2 publications found

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009886026).
• BP6: Variant 10-53807001-C-T is Benign according to our data. Variant chr10-53807001-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227836.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_001384140.1	MANE Select	c.4801G>A	p.Gly1601Ser	missense	Exon 38 of 38	NP_001371069.1
	PCDH15	NM_001354429.2		c.4735G>A	p.Gly1579Ser	missense	Exon 37 of 37	NP_001341358.1
	PCDH15	NM_001142771.2		c.4627G>A	p.Gly1543Ser	missense	Exon 36 of 36	NP_001136243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000644397.2	MANE Select	c.4801G>A	p.Gly1601Ser	missense	Exon 38 of 38	ENSP00000495195.1
	PCDH15	ENST00000616114.4	TSL:1	c.4606G>A	p.Gly1536Ser	missense	Exon 34 of 34	ENSP00000483745.1
	PCDH15	ENST00000621708.4	TSL:5	c.4627G>A	p.Gly1543Ser	missense	Exon 36 of 36	ENSP00000484454.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00431

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

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: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000326 AC: 81 AN: 248194 AF XY: 0.000230

Gnomad AFR exome AF: 0.00428

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1461450 Hom.: 1 Cov.: 33 AF XY: 0.000127 AC XY: 92 AN XY: 727004

African (AFR) AF: 0.00460 AC: 154 AN: 33470

American (AMR) AF: 0.000291 AC: 13 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111704

Other (OTH) AF: 0.000282 AC: 17 AN: 60366

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74296

African (AFR) AF: 0.00429 AC: 178 AN: 41468

American (AMR) AF: 0.000722 AC: 11 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67966

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000731 Hom.: 1

Bravo AF: 0.00166

ESP6500AA AF: 0.00542 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000365 AC: 44

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	1	PCDH15-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0099	T
MetaSVM	Uncertain	-0.24	T
PhyloP100		4.8
REVEL	Benign	0.25
Sift4G	Benign	0.25	T
Vest4		0.20
MVP		0.78
ClinPred		0.054	T
GERP RS		5.9
Mutation Taster		=40/60	disease causing

Splicing

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

Other links and lift over

dbSNP: rs181306086; hg19: chr10-55566761; COSMIC: COSV100905036; COSMIC: COSV100905036;