rs139409005

Variant names:

• chr10-71797200-G-A
• rs139409005
• NM_022124.6:c.6809G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71797200-G-A
• chr10-71797200-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_022124.6(CDH23):​c.6809G>A​(p.Arg2270His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000598 in 1,612,490 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2270C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.591
• Publications: 8 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02303636).
• BP6: Variant 10-71797200-G-A is Benign according to our data. Variant chr10-71797200-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178310.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000623 (910/1460192) while in subpopulation AMR AF = 0.00103 (46/44606). AF 95% confidence interval is 0.000794. There are 0 homozygotes in GnomAdExome4. There are 441 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.6809G>A	p.Arg2270His	missense	Exon 49 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.89G>A	p.Arg30His	missense	Exon 2 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.89G>A	p.Arg30His	missense	Exon 2 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.6809G>A	p.Arg2270His	missense	Exon 49 of 70	ENSP00000224721.9
	CDH23	ENST00000398788.4	TSL:1	c.89G>A	p.Arg30His	missense	Exon 2 of 23	ENSP00000381768.3
	CDH23	ENST00000619887.4	TSL:1	c.89G>A	p.Arg30His	missense	Exon 2 of 22	ENSP00000478374.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000384 AC: 95 AN: 247258 AF XY: 0.000328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000473

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000623 AC: 910 AN: 1460192 Hom.: 0 Cov.: 30 AF XY: 0.000607 AC XY: 441 AN XY: 726284

African (AFR) AF: 0.000120 AC: 4 AN: 33454

American (AMR) AF: 0.00103 AC: 46 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39688

South Asian (SAS) AF: 0.000163 AC: 14 AN: 85930

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53294

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.000720 AC: 800 AN: 1111024

Other (OTH) AF: 0.000597 AC: 36 AN: 60328

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74476

African (AFR) AF: 0.000168 AC: 7 AN: 41568

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68020

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000553 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000265 AC: 32

EpiCase AF: 0.000382

EpiControl AF: 0.000655

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L
PhyloP100		-0.59
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.028
Sift	Benign	0.19	T
Sift4G	Uncertain	0.017	D
Polyphen		0.0040	B
Vest4		0.11
MVP		0.61
MPC		0.18
ClinPred		0.033	T
GERP RS		-1.7
Varity_R		0.055
gMVP		0.32
Mutation Taster		=97/3	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: rs139409005; hg19: chr10-73556957; COSMIC: COSV56478018;