rs77821631

Variant names:

• chr10-71712808-T-G
• rs77821631
• NM_022124.6:c.3364T>G
• CDH23 p.Leu1122Val

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.3364T>G​(p.Leu1122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,611,752 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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. L1122F) has been classified as Uncertain significance. The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0068 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (9 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.56
• Publications: 2 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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.005255878).
• BP6: Variant 10-71712808-T-G is Benign according to our data. Variant chr10-71712808-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45917.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00677 (1032/152350) while in subpopulation AFR AF = 0.0236 (980/41598). AF 95% confidence interval is 0.0223. There are 15 homozygotes in GnomAd4. There are 475 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,Unknown 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.3364T>G	p.Leu1122Val	missense	Exon 28 of 70	NP_071407.4
	C10orf105	NM_001164375.3	MANE Select	c.*3128A>C		3_prime_UTR	Exon 2 of 2	NP_001157847.1	Q8TEF2
	CDH23	NM_001171930.2		c.3364T>G	p.Leu1122Val	missense	Exon 28 of 32	NP_001165401.1	A0A087WYR8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3364T>G	p.Leu1122Val	missense	Exon 28 of 70	ENSP00000224721.9	Q9H251-1
	C10orf105	ENST00000441508.4	TSL:1 MANE Select	c.*3128A>C		3_prime_UTR	Exon 2 of 2	ENSP00000403151.2	Q8TEF2
	CDH23	ENST00000616684.4	TSL:5	c.3364T>G	p.Leu1122Val	missense	Exon 28 of 32	ENSP00000482036.2	A0A087WYR8

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1027 AN: 152232 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00168 AC: 409 AN: 242938 AF XY: 0.00115

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.000998

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000845

GnomAD4 exome AF: 0.000662 AC: 966 AN: 1459402 Hom.: 9 Cov.: 31 AF XY: 0.000517 AC XY: 375 AN XY: 725778

African (AFR) AF: 0.0231 AC: 772 AN: 33448

American (AMR) AF: 0.00119 AC: 53 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000933 AC: 8 AN: 85740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52778

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111234

Other (OTH) AF: 0.00184 AC: 111 AN: 60286

GnomAD4 genome AF: 0.00677 AC: 1032 AN: 152350 Hom.: 15 Cov.: 33 AF XY: 0.00638 AC XY: 475 AN XY: 74502

African (AFR) AF: 0.0236 AC: 980 AN: 41598

American (AMR) AF: 0.00209 AC: 32 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00200 Hom.: 5

Bravo AF: 0.00711

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (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	0.059
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.9
DANN	Benign	0.89
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	N
PhyloP100		2.6
PrimateAI	Benign	0.41	T
REVEL	Benign	0.064
Sift4G	Benign	1.0	T
Varity_R		0.059
gMVP		0.26
Mutation Taster		=91/9	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77821631;

hg19: chr10-73472565;