rs376560330

Variant names:

• chr10-71705068-G-A
• rs376560330
• NM_022124.6:c.2891G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71705068-G-A
• chr10-71705068-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.2891G>A​(p.Arg964Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,612,522 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R964W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (9 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 9.96
• Publications: 5 publications found

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300551 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_022124.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.031760544).
• BP6: Variant 10-71705068-G-A is Benign according to our data. Variant chr10-71705068-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45905.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000164 (25/152254) while in subpopulation EAS AF = 0.00348 (18/5168). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. 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
	CDH23	NM_022124.6	MANE Select	c.2891G>A	p.Arg964Gln	missense	Exon 25 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.2891G>A	p.Arg964Gln	missense	Exon 25 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.2891G>A	p.Arg964Gln	missense	Exon 25 of 26	NP_001165402.1	Q8N5B3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2891G>A	p.Arg964Gln	missense	Exon 25 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.2891G>A	p.Arg964Gln	missense	Exon 25 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.2891G>A	p.Arg964Gln	missense	Exon 25 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000216 AC: 53 AN: 245376 AF XY: 0.000186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00207

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000165 AC: 241 AN: 1460268 Hom.: 9 Cov.: 32 AF XY: 0.000124 AC XY: 90 AN XY: 726468

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000895 AC: 4 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00141 AC: 56 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111792

Other (OTH) AF: 0.00262 AC: 158 AN: 60356

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74442

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.000327 AC: 5 AN: 15308

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

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.000268

ExAC AF: 0.000240 AC: 29

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	CDH23-related disorder (1)
-	-	1	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.43	N
PhyloP100		10
PrimateAI	Uncertain	0.49	T
REVEL	Uncertain	0.41
Sift4G	Uncertain	0.057	T
Polyphen		0.98	D
Vest4		0.84
MVP		0.72
ClinPred		0.14	T
GERP RS		5.5
Varity_R		0.31
gMVP		0.56
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs376560330; hg19: chr10-73464825; COSMIC: COSV54941137;