rs17704703

Variant names:

• chr10-53806646-T-G
• rs17704703
• NM_001384140.1:c.5156A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-53806646-T-G
• chr10-53806646-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384140.1(PCDH15):​c.5156A>C​(p.Gln1719Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,326 control chromosomes in the GnomAD database, including 63,781 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3936 hom., cov: 32)
  • Exomes 𝑓: 0.27 (59845 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.58
• Publications: 19 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 Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Usher syndrome type 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004988849).
• BP6: Variant 10-53806646-T-G is Benign according to our data. Variant chr10-53806646-T-G is described in ClinVar as Benign. ClinVar VariationId is 227005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_001384140.1	MANE Select	c.5156A>C	p.Gln1719Pro	missense	Exon 38 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001354429.2		c.5090A>C	p.Gln1697Pro	missense	Exon 37 of 37	NP_001341358.1
	PCDH15	NM_001142771.2		c.4982A>C	p.Gln1661Pro	missense	Exon 36 of 36	NP_001136243.1	A0A087X1T6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000644397.2	MANE Select	c.5156A>C	p.Gln1719Pro	missense	Exon 38 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000616114.4	TSL:1	c.4961A>C	p.Gln1654Pro	missense	Exon 34 of 34	ENSP00000483745.1	Q96QU1-6
	PCDH15	ENST00000621708.4	TSL:5	c.4982A>C	p.Gln1661Pro	missense	Exon 36 of 36	ENSP00000484454.1	A0A087X1T6

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30172 AN: 151958 Hom.: 3939 Cov.: 32

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.212 AC: 52654 AN: 248680 AF XY: 0.218

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.00134

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.275 AC: 401654 AN: 1461250 Hom.: 59845 Cov.: 35 AF XY: 0.273 AC XY: 198384 AN XY: 726934

African (AFR) AF: 0.0476 AC: 1592 AN: 33466

American (AMR) AF: 0.122 AC: 5454 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 5433 AN: 26126

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39700

South Asian (SAS) AF: 0.178 AC: 15345 AN: 86252

European-Finnish (FIN) AF: 0.272 AC: 14543 AN: 53402

Middle Eastern (MID) AF: 0.237 AC: 1366 AN: 5768

European-Non Finnish (NFE) AF: 0.309 AC: 343199 AN: 1111482

Other (OTH) AF: 0.243 AC: 14697 AN: 60360

GnomAD4 genome AF: 0.198 AC: 30160 AN: 152076 Hom.: 3936 Cov.: 32 AF XY: 0.193 AC XY: 14360 AN XY: 74336

African (AFR) AF: 0.0560 AC: 2325 AN: 41550

American (AMR) AF: 0.166 AC: 2533 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 706 AN: 3470

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5170

South Asian (SAS) AF: 0.175 AC: 844 AN: 4820

European-Finnish (FIN) AF: 0.257 AC: 2714 AN: 10560

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20351 AN: 67922

Other (OTH) AF: 0.200 AC: 422 AN: 2110

Alfa AF: 0.250 Hom.: 11666

Bravo AF: 0.182

TwinsUK AF: 0.307 AC: 1137

ALSPAC AF: 0.292 AC: 1125

ESP6500AA AF: 0.0609 AC: 191

ESP6500EA AF: 0.295 AC: 2114

ExAC AF: 0.212 AC: 25570

Asia WGS AF: 0.0830 AC: 291 AN: 3478

EpiCase AF: 0.292

EpiControl AF: 0.289

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1F (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 23 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.6
REVEL	Benign	0.039
Sift4G	Benign	0.083	T
Vest4		0.18
ClinPred		0.0056	T
GERP RS		3.6
Mutation Taster		=52/48	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs17704703; hg19: chr10-55566406; COSMIC: COSV108215569; COSMIC: COSV108215569;