rs41281338

Variant names:

• chr10-71803310-G-C
• rs41281338
• NM_022124.6:c.7762G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-71803310-G-C
• chr10-71803310-G-T

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.7762G>C​(p.Glu2588Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00972 in 1,591,622 control chromosomes in the GnomAD database, including 124 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2588D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (7 hom., cov: 31)
  • Exomes 𝑓: 0.010 (117 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.00300
• Publications: 9 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=0.0042585135).
• BP6: Variant 10-71803310-G-C is Benign according to our data. Variant chr10-71803310-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46038.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00726 (1105/152290) while in subpopulation SAS AF = 0.0207 (100/4822). AF 95% confidence interval is 0.0174. There are 7 homozygotes in GnomAd4. There are 546 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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.7762G>C	p.Glu2588Gln	missense	Exon 55 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.1042G>C	p.Glu348Gln	missense	Exon 8 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.1042G>C	p.Glu348Gln	missense	Exon 8 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.7762G>C	p.Glu2588Gln	missense	Exon 55 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.1298G>C		non_coding_transcript_exon	Exon 7 of 21
	CDH23	ENST00000642965.1		n.*1605G>C		non_coding_transcript_exon	Exon 10 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.00727 AC: 1107 AN: 152172 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00907 AC: 1900 AN: 209470 AF XY: 0.0102

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00362

Gnomad ASJ exome AF: 0.00538

Gnomad EAS exome AF: 0.000199

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00878

GnomAD4 exome AF: 0.00998 AC: 14361 AN: 1439332 Hom.: 117 Cov.: 34 AF XY: 0.0105 AC XY: 7470 AN XY: 713934

African (AFR) AF: 0.00131 AC: 43 AN: 32792

American (AMR) AF: 0.00363 AC: 152 AN: 41870

Ashkenazi Jewish (ASJ) AF: 0.00565 AC: 145 AN: 25666

East Asian (EAS) AF: 0.0000524 AC: 2 AN: 38198

South Asian (SAS) AF: 0.0237 AC: 1966 AN: 82854

European-Finnish (FIN) AF: 0.00420 AC: 217 AN: 51698

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5744

European-Non Finnish (NFE) AF: 0.0101 AC: 11173 AN: 1100954

Other (OTH) AF: 0.00934 AC: 556 AN: 59556

GnomAD4 genome AF: 0.00726 AC: 1105 AN: 152290 Hom.: 7 Cov.: 31 AF XY: 0.00733 AC XY: 546 AN XY: 74478

African (AFR) AF: 0.00159 AC: 66 AN: 41562

American (AMR) AF: 0.00608 AC: 93 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4822

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 769 AN: 68010

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00981 Hom.: 9

Bravo AF: 0.00634

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00146 AC: 6

ESP6500EA AF: 0.0115 AC: 96

ExAC AF: 0.00840 AC: 1013

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	not provided (2)
-	-	2	not specified (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	0.057
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.49
DEOGEN2	Benign	0.0083	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.84	L
PhyloP100		-0.0030
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.072
Sift	Benign	0.58	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.33
MPC		0.14
ClinPred		0.00013	T
GERP RS		-2.6
Varity_R		0.097
gMVP		0.23
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: rs41281338; hg19: chr10-73563067; COSMIC: COSV99034499;