chr10-71617355-G-A

Variant names:

• chr10-71617355-G-A
• rs143282422
• NM_022124.6:c.1096G>A

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.1096G>A​(p.Ala366Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00923 in 1,613,862 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts 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. A366A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0065 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (128 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:14
• Conservation: PhyloP100: 9.24
• Publications: 28 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008493274).
• BP6: Variant 10-71617355-G-A is Benign according to our data. Variant chr10-71617355-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44114.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00653 (994/152264) while in subpopulation NFE AF = 0.00912 (620/68016). AF 95% confidence interval is 0.00852. There are 7 homozygotes in GnomAd4. There are 434 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.1096G>A	p.Ala366Thr	missense	Exon 11 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.1096G>A	p.Ala366Thr	missense	Exon 11 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.1096G>A	p.Ala366Thr	missense	Exon 11 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.1096G>A	p.Ala366Thr	missense	Exon 11 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.1096G>A	p.Ala366Thr	missense	Exon 11 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.1096G>A	p.Ala366Thr	missense	Exon 11 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 994 AN: 152146 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00732 AC: 1825 AN: 249204 AF XY: 0.00726

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.0487

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000979

Gnomad NFE exome AF: 0.00898

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00952 AC: 13910 AN: 1461598 Hom.: 128 Cov.: 31 AF XY: 0.00943 AC XY: 6857 AN XY: 727090

African (AFR) AF: 0.00167 AC: 56 AN: 33480

American (AMR) AF: 0.00517 AC: 231 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0535 AC: 1399 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00210 AC: 181 AN: 86256

European-Finnish (FIN) AF: 0.00128 AC: 68 AN: 53300

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.0102 AC: 11311 AN: 1111864

Other (OTH) AF: 0.0104 AC: 627 AN: 60370

GnomAD4 genome AF: 0.00653 AC: 994 AN: 152264 Hom.: 7 Cov.: 32 AF XY: 0.00583 AC XY: 434 AN XY: 74450

African (AFR) AF: 0.00202 AC: 84 AN: 41542

American (AMR) AF: 0.00542 AC: 83 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3470

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

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4810

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00912 AC: 620 AN: 68016

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.0100 Hom.: 39

Bravo AF: 0.00730

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00389 AC: 17

ESP6500EA AF: 0.0103 AC: 88

ExAC AF: 0.00696 AC: 844

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00965

EpiControl AF: 0.0107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	6	not specified (6)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Nonsyndromic genetic hearing loss (1)
-	1	-	Retinal dystrophy (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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0025	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.41	N
PhyloP100		9.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.20
Sift	Benign	0.14	T
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.79
MVP		0.76
ClinPred		0.032	T
GERP RS		5.2
PromoterAI		-0.0044	Neutral
Varity_R		0.30
gMVP		0.40
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143282422; hg19: chr10-73377112;