10-71798371-G-A

Variant names:

• chr10-71798371-G-A
• rs41281334
• NM_022124.6:c.6847G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.6847G>A​(p.Val2283Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0457 in 1,613,470 control chromosomes in the GnomAD database, including 2,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2283L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.038 (165 hom., cov: 32)
  • Exomes 𝑓: 0.046 (2057 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 3.95
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013784468).
• BP6: Variant 10-71798371-G-A is Benign according to our data. Variant chr10-71798371-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0899 is higher than 0.05.

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.6847G>A	p.Val2283Ile	missense	Exon 50 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.127G>A	p.Val43Ile	missense	Exon 3 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.127G>A	p.Val43Ile	missense	Exon 3 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.6847G>A	p.Val2283Ile	missense	Exon 50 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.383G>A		non_coding_transcript_exon	Exon 2 of 21
	CDH23	ENST00000642965.1		n.*690G>A		non_coding_transcript_exon	Exon 5 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5859 AN: 152140 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0937

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0453

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0554 AC: 13802 AN: 249244 AF XY: 0.0504

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0412

Gnomad OTH exome AF: 0.0562

GnomAD4 exome AF: 0.0465 AC: 67919 AN: 1461212 Hom.: 2057 Cov.: 32 AF XY: 0.0451 AC XY: 32779 AN XY: 726942

African (AFR) AF: 0.00851 AC: 285 AN: 33474

American (AMR) AF: 0.165 AC: 7376 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 280 AN: 26132

East Asian (EAS) AF: 0.0339 AC: 1347 AN: 39698

South Asian (SAS) AF: 0.0276 AC: 2380 AN: 86250

European-Finnish (FIN) AF: 0.0393 AC: 2096 AN: 53400

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5766

European-Non Finnish (NFE) AF: 0.0465 AC: 51630 AN: 1111418

Other (OTH) AF: 0.0409 AC: 2467 AN: 60358

GnomAD4 genome AF: 0.0385 AC: 5860 AN: 152258 Hom.: 165 Cov.: 32 AF XY: 0.0385 AC XY: 2864 AN XY: 74452

African (AFR) AF: 0.0104 AC: 432 AN: 41536

American (AMR) AF: 0.0939 AC: 1437 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.0434 AC: 225 AN: 5180

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4828

European-Finnish (FIN) AF: 0.0335 AC: 356 AN: 10612

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0453 AC: 3082 AN: 68010

Other (OTH) AF: 0.0336 AC: 71 AN: 2114

Alfa AF: 0.0415 Hom.: 609

Bravo AF: 0.0450

TwinsUK AF: 0.0526 AC: 195

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.0102 AC: 44

ESP6500EA AF: 0.0459 AC: 391

ExAC AF: 0.0493 AC: 5979

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.0405

EpiControl AF: 0.0399

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (4)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.2
DANN	Benign	0.27
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.057
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		0.014	B
Vest4		0.077
MPC		0.12
ClinPred		0.0024	T
GERP RS		3.2
Varity_R		0.036
gMVP		0.21
Mutation Taster		=95/5	polymorphism (auto)

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: rs41281334; hg19: chr10-73558128;