chr10-71803066-C-G

Variant names:

• chr10-71803066-C-G
• rs548188123
• NM_022124.6:c.7651C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022124.6(CDH23):​c.7651C>G​(p.Pro2551Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.30
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28985476).

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.7651C>G	p.Pro2551Ala	missense	Exon 54 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.931C>G	p.Pro311Ala	missense	Exon 7 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.931C>G	p.Pro311Ala	missense	Exon 7 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.7651C>G	p.Pro2551Ala	missense	Exon 54 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.1187C>G		non_coding_transcript_exon	Exon 6 of 21
	CDH23	ENST00000642965.1		n.*1494C>G		non_coding_transcript_exon	Exon 9 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248234 AF XY: 0.00000743

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457476 Hom.: 0 Cov.: 38 AF XY: 0.00000276 AC XY: 2 AN XY: 724140

African (AFR) AF: 0.0000599 AC: 2 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108466

Other (OTH) AF: 0.00 AC: 0 AN: 60142

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.82	L
PhyloP100		5.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.25
Sift	Benign	0.48	T
Sift4G	Uncertain	0.015	D
Polyphen		0.71	P
Vest4		0.48
MutPred		0.55		Loss of disorder (P = 0.0888)
MVP		0.88
MPC		0.46
ClinPred		0.53	D
GERP RS		5.0
Varity_R		0.12
gMVP		0.17
Mutation Taster		=29/71	disease causing

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: rs548188123; hg19: chr10-73562823;