rs3812658

Variant names:

• chr10-54020155-G-A
• rs3812658
• NM_033056.4:c.2751+37C>T

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.2751+37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,578,954 control chromosomes in the GnomAD database, including 390,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (29492 hom., cov: 31)
  • Exomes 𝑓: 0.70 (360905 hom.)
• Consequence: PCDH15 NM_001384140.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.118
• Publications: 9 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 (BayesDel_noAF=-0.87).
• BP6: Variant 10-54020155-G-A is Benign according to our data. Variant chr10-54020155-G-A is described in ClinVar as Benign. ClinVar VariationId is 262147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.736 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_033056.4	MANE Plus Clinical	c.2751+37C>T		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.2751+37C>T		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.2766+37C>T		intron	N/A	NP_001136235.1	A2A3D8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.2751+37C>T		intron	N/A	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.2751+37C>T		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.2772+37C>T		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.593 AC: 89924 AN: 151724 Hom.: 29489 Cov.: 31

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.642

GnomAD2 exomes AF: 0.647 AC: 160334 AN: 247826 AF XY: 0.646

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.745

Gnomad ASJ exome AF: 0.740

Gnomad EAS exome AF: 0.336

Gnomad FIN exome AF: 0.689

Gnomad NFE exome AF: 0.744

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.701 AC: 1000658 AN: 1427112 Hom.: 360905 Cov.: 25 AF XY: 0.696 AC XY: 495701 AN XY: 712210

African (AFR) AF: 0.305 AC: 9944 AN: 32612

American (AMR) AF: 0.741 AC: 32963 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 19291 AN: 25918

East Asian (EAS) AF: 0.275 AC: 10841 AN: 39442

South Asian (SAS) AF: 0.483 AC: 41253 AN: 85444

European-Finnish (FIN) AF: 0.692 AC: 36505 AN: 52718

Middle Eastern (MID) AF: 0.755 AC: 4305 AN: 5704

European-Non Finnish (NFE) AF: 0.745 AC: 805579 AN: 1081534

Other (OTH) AF: 0.675 AC: 39977 AN: 59244

GnomAD4 genome AF: 0.592 AC: 89935 AN: 151842 Hom.: 29492 Cov.: 31 AF XY: 0.589 AC XY: 43672 AN XY: 74208

African (AFR) AF: 0.318 AC: 13167 AN: 41428

American (AMR) AF: 0.702 AC: 10689 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2552 AN: 3468

East Asian (EAS) AF: 0.292 AC: 1505 AN: 5152

South Asian (SAS) AF: 0.463 AC: 2232 AN: 4822

European-Finnish (FIN) AF: 0.690 AC: 7278 AN: 10550

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.742 AC: 50351 AN: 67894

Other (OTH) AF: 0.636 AC: 1340 AN: 2108

Alfa AF: 0.702 Hom.: 49492

Bravo AF: 0.587

Asia WGS AF: 0.361 AC: 1255 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.19
PhyloP100		-0.12
Mutation Taster		=100/0	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: rs3812658; hg19: chr10-55779915; COSMIC: COSV57320711;