rs188098974

Variant names:

• chr10-71705007-A-G
• rs188098974
• NM_022124.6:c.2830A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-71705007-A-G
• chr10-71705007-A-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.2830A>G​(p.Ser944Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00102 in 1,612,704 control chromosomes in the GnomAD database, including 9 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. S944S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00095 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 5.16
• Publications: 10 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

ENSG00000300551 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.01838386).
• BP6: Variant 10-71705007-A-G is Benign according to our data. Variant chr10-71705007-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45902.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000946 (144/152154) while in subpopulation SAS AF = 0.00291 (14/4814). AF 95% confidence interval is 0.00176. There are 2 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.2830A>G	p.Ser944Gly	missense	Exon 25 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.2830A>G	p.Ser944Gly	missense	Exon 25 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.2830A>G	p.Ser944Gly	missense	Exon 25 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.2830A>G	p.Ser944Gly	missense	Exon 25 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.2830A>G	p.Ser944Gly	missense	Exon 25 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.2830A>G	p.Ser944Gly	missense	Exon 25 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.000947 AC: 144 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00121 AC: 300 AN: 247458 AF XY: 0.00136

Gnomad AFR exome AF: 0.0000653

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.00102 AC: 1497 AN: 1460550 Hom.: 7 Cov.: 32 AF XY: 0.00117 AC XY: 848 AN XY: 726570

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00296 AC: 255 AN: 86258

European-Finnish (FIN) AF: 0.00273 AC: 143 AN: 52286

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000908 AC: 1010 AN: 1111842

Other (OTH) AF: 0.000961 AC: 58 AN: 60360

GnomAD4 genome AF: 0.000946 AC: 144 AN: 152154 Hom.: 2 Cov.: 32 AF XY: 0.000995 AC XY: 74 AN XY: 74394

African (AFR) AF: 0.0000241 AC: 1 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4814

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 67970

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00128 Hom.: 2

Bravo AF: 0.000544

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000951 AC: 8

ExAC AF: 0.00134 AC: 162

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	not specified (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	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.2
PrimateAI	Benign	0.39	T
REVEL	Benign	0.18
Sift4G	Uncertain	0.0040	D
Polyphen		0.014	B
Vest4		0.29
MVP		0.88
ClinPred		0.081	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.29
Mutation Taster		=87/13	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: rs188098974; hg19: chr10-73464764;