10-71806270-G-C

Variant names:

• chr10-71806270-G-C
• rs142857685
• NM_022124.6:c.8167G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022124.6(CDH23):​c.8167G>C​(p.Val2723Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,557,966 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V2723V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 1.15
• 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, PanelApp Australia
• nonsyndromic genetic hearing loss

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

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008520603).
• BP6: Variant 10-71806270-G-C is Benign according to our data. Variant chr10-71806270-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46045.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00104 (159/152164) while in subpopulation AFR AF = 0.00308 (128/41492). AF 95% confidence interval is 0.00265. There are 3 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.8167G>C	p.Val2723Leu	missense	Exon 57 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.1447G>C	p.Val483Leu	missense	Exon 10 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.1447G>C	p.Val483Leu	missense	Exon 10 of 22	NP_001165405.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.8167G>C	p.Val2723Leu	missense	Exon 57 of 70	ENSP00000224721.9
	CDH23	ENST00000398788.4	TSL:1	c.1447G>C	p.Val483Leu	missense	Exon 10 of 23	ENSP00000381768.3
	CDH23	ENST00000619887.4	TSL:1	c.1447G>C	p.Val483Leu	missense	Exon 10 of 22	ENSP00000478374.1

Frequencies

GnomAD3 genomes AF: 0.000987 AC: 150 AN: 152046 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000297 AC: 49 AN: 165162 AF XY: 0.000228

Gnomad AFR exome AF: 0.00334

Gnomad AMR exome AF: 0.000313

Gnomad ASJ exome AF: 0.000230

Gnomad EAS exome AF: 0.0000857

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000593

Gnomad OTH exome AF: 0.000867

GnomAD4 exome AF: 0.000176 AC: 248 AN: 1405802 Hom.: 2 Cov.: 31 AF XY: 0.000171 AC XY: 119 AN XY: 694502

African (AFR) AF: 0.00347 AC: 111 AN: 32030

American (AMR) AF: 0.000353 AC: 13 AN: 36792

Ashkenazi Jewish (ASJ) AF: 0.000277 AC: 7 AN: 25282

East Asian (EAS) AF: 0.0000549 AC: 2 AN: 36412

South Asian (SAS) AF: 0.0000251 AC: 2 AN: 79744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47790

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5710

European-Non Finnish (NFE) AF: 0.0000544 AC: 59 AN: 1083634

Other (OTH) AF: 0.000753 AC: 44 AN: 58408

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152164 Hom.: 3 Cov.: 31 AF XY: 0.00109 AC XY: 81 AN XY: 74388

African (AFR) AF: 0.00308 AC: 128 AN: 41492

American (AMR) AF: 0.00131 AC: 20 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000485 Hom.: 1

Bravo AF: 0.00117

ESP6500AA AF: 0.00213 AC: 9

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000217 AC: 25

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (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	0.078
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.040	N
PhyloP100		1.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.34		Gain of sheet (P = 0.0221)
MVP		0.70
MPC		0.14
ClinPred		0.015	T
GERP RS		3.3
Varity_R		0.041
gMVP		0.23
Mutation Taster		=88/12	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: rs142857685; hg19: chr10-73566027;