NM_022124.6:c.3845A>G

Variant names:

• chr10-71732116-A-G
• rs149073355
• NM_022124.6:c.3845A>G

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.3845A>G​(p.Asn1282Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,613,988 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (21 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 7.22
• 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]

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.012104154).
• BP6: Variant 10-71732116-A-G is Benign according to our data. Variant chr10-71732116-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45931.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00333 (507/152286) while in subpopulation NFE AF = 0.00585 (398/68010). AF 95% confidence interval is 0.00538. There are 1 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.3845A>G	p.Asn1282Ser	missense	Exon 32 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3845A>G	p.Asn1282Ser	missense	Exon 32 of 32	NP_001165401.1	A0A087WYR8
	C10orf105	NM_001168390.2		c.-6+5612T>C		intron	N/A	NP_001161862.1	Q8TEF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3845A>G	p.Asn1282Ser	missense	Exon 32 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.3845A>G	p.Asn1282Ser	missense	Exon 32 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.3842A>G	p.Asn1281Ser	missense	Exon 32 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00585

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00293 AC: 731 AN: 249260 AF XY: 0.00296

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00532

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00529 AC: 7726 AN: 1461702 Hom.: 21 Cov.: 31 AF XY: 0.00504 AC XY: 3668 AN XY: 727136

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00143 AC: 64 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00257 AC: 137 AN: 53400

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00647 AC: 7192 AN: 1111866

Other (OTH) AF: 0.00485 AC: 293 AN: 60374

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74470

African (AFR) AF: 0.00118 AC: 49 AN: 41566

American (AMR) AF: 0.00196 AC: 30 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00585 AC: 398 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00483 Hom.: 7

Bravo AF: 0.00332

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000933 AC: 4

ESP6500EA AF: 0.00473 AC: 40

ExAC AF: 0.00281 AC: 340

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00522

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	1	-	Meniere disease (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	0.14
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.20	N
PhyloP100		7.2
PrimateAI	Uncertain	0.61	T
REVEL	Uncertain	0.34
Sift4G	Uncertain	0.040	D
Polyphen		0.93	P
Vest4		0.76
MVP		0.68
ClinPred		0.046	T
GERP RS		4.8
Varity_R		0.30
gMVP		0.25
Mutation Taster		=75/25	polymorphism

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: rs149073355; hg19: chr10-73491873; COSMIC: COSV106081740;