rs746121407

Variant names:

• chr10-71807995-G-A
• rs746121407
• NM_022124.6:c.8710G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71807995-G-A
• chr10-71807995-G-C
• chr10-71807995-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022124.6(CDH23):​c.8710G>A​(p.Val2904Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2904F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.28
• Publications: 2 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15456036).

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.8710G>A	p.Val2904Ile	missense	Exon 60 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.1990G>A	p.Val664Ile	missense	Exon 13 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.1990G>A	p.Val664Ile	missense	Exon 13 of 22	NP_001165405.1	Q9H251-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.8710G>A	p.Val2904Ile	missense	Exon 60 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.2246G>A		non_coding_transcript_exon	Exon 12 of 21
	CDH23	ENST00000642965.1		n.*2553G>A		non_coding_transcript_exon	Exon 15 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.12
Sift	Uncertain	0.018	D
Sift4G	Benign	1.0	T
Polyphen		0.014	B
Vest4		0.088
MutPred		0.47		Loss of sheet (P = 0.1398)
MVP		0.76
MPC		0.12
ClinPred		0.39	T
GERP RS		5.3
Varity_R		0.032
gMVP		0.14
Mutation Taster		=84/16	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: rs746121407; hg19: chr10-73567752;