rs149481989

Variant names:

• chr10-54236866-T-C
• rs149481989
• NM_033056.4:c.942A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-54236866-T-C
• chr10-54236866-T-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001384140.1(PCDH15):​c.942A>G​(p.Gln314Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,613,692 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: PCDH15 NM_001384140.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0510
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 10-54236866-T-C is Benign according to our data. Variant chr10-54236866-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178522.
• BP7: Synonymous conserved (PhyloP=-0.051 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Unknown gene

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.942A>G	p.Gln314Gln	synonymous	Exon 9 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.942A>G	p.Gln314Gln	synonymous	Exon 9 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.957A>G	p.Gln319Gln	synonymous	Exon 10 of 35	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.942A>G	p.Gln314Gln	synonymous	Exon 9 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.942A>G	p.Gln314Gln	synonymous	Exon 9 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.942A>G	p.Gln314Gln	synonymous	Exon 9 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.000395 AC: 60 AN: 152080 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000378 AC: 95 AN: 251398 AF XY: 0.000397

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1461494 Hom.: 2 Cov.: 31 AF XY: 0.000168 AC XY: 122 AN XY: 727056

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00283 AC: 151 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000765 AC: 85 AN: 1111718

Other (OTH) AF: 0.000199 AC: 12 AN: 60374

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000632 AC XY: 47 AN XY: 74408

African (AFR) AF: 0.0000481 AC: 2 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00481 AC: 51 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.6
DANN	Benign	0.43
PhyloP100		-0.051
Mutation Taster		=95/5	polymorphism

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: rs149481989; hg19: chr10-55996626;