rs1227065

Variant names:

• chr10-71732322-A-G
• rs1227065
• NM_022124.6:c.4051A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-71732322-A-G
• chr10-71732322-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.4051A>G​(p.Asn1351Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.807 in 1,599,966 control chromosomes in the GnomAD database, including 521,105 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1351N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.80 (48634 hom., cov: 33)
  • Exomes 𝑓: 0.81 (472471 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 7.75
• Publications: 46 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1604471E-6).
• BP6: Variant 10-71732322-A-G is Benign according to our data. Variant chr10-71732322-A-G is described in ClinVar as Benign. ClinVar VariationId is 45937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

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.4051A>G	p.Asn1351Asp	missense	Exon 32 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.4051A>G	p.Asn1351Asp	missense	Exon 32 of 32	NP_001165401.1	A0A087WYR8
	C10orf105	NM_001168390.2		c.-6+5406T>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.4051A>G	p.Asn1351Asp	missense	Exon 32 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.4051A>G	p.Asn1351Asp	missense	Exon 32 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.4048A>G	p.Asn1350Asp	missense	Exon 32 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121582 AN: 152062 Hom.: 48603 Cov.: 33

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.800

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.805

GnomAD2 exomes AF: 0.807 AC: 183095 AN: 226914 AF XY: 0.808

Gnomad AFR exome AF: 0.767

Gnomad AMR exome AF: 0.794

Gnomad ASJ exome AF: 0.856

Gnomad EAS exome AF: 0.846

Gnomad FIN exome AF: 0.756

Gnomad NFE exome AF: 0.817

Gnomad OTH exome AF: 0.816

GnomAD4 exome AF: 0.808 AC: 1169142 AN: 1447786 Hom.: 472471 Cov.: 69 AF XY: 0.808 AC XY: 580806 AN XY: 718984

African (AFR) AF: 0.763 AC: 25282 AN: 33154

American (AMR) AF: 0.789 AC: 33439 AN: 42398

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 22191 AN: 25870

East Asian (EAS) AF: 0.831 AC: 32400 AN: 38976

South Asian (SAS) AF: 0.800 AC: 67403 AN: 84304

European-Finnish (FIN) AF: 0.757 AC: 39699 AN: 52442

Middle Eastern (MID) AF: 0.824 AC: 4744 AN: 5754

European-Non Finnish (NFE) AF: 0.811 AC: 895602 AN: 1104964

Other (OTH) AF: 0.807 AC: 48382 AN: 59924

GnomAD4 genome AF: 0.799 AC: 121662 AN: 152180 Hom.: 48634 Cov.: 33 AF XY: 0.797 AC XY: 59265 AN XY: 74382

African (AFR) AF: 0.776 AC: 32220 AN: 41494

American (AMR) AF: 0.799 AC: 12222 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 3001 AN: 3472

East Asian (EAS) AF: 0.832 AC: 4311 AN: 5182

South Asian (SAS) AF: 0.801 AC: 3857 AN: 4816

European-Finnish (FIN) AF: 0.754 AC: 7990 AN: 10594

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55394 AN: 68006

Other (OTH) AF: 0.807 AC: 1705 AN: 2112

Alfa AF: 0.815 Hom.: 244392

Bravo AF: 0.803

TwinsUK AF: 0.816 AC: 3027

ALSPAC AF: 0.812 AC: 3128

ESP6500AA AF: 0.791 AC: 3275

ESP6500EA AF: 0.824 AC: 6922

ExAC AF: 0.794 AC: 95662

Asia WGS AF: 0.798 AC: 2775 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Retinitis pigmentosa-deafness syndrome (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.52
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.61	N
PhyloP100		7.8
PrimateAI	Uncertain	0.52	T
REVEL	Benign	0.15
Sift4G	Benign	1.0	T
Vest4		0.20
ClinPred		0.022	T
GERP RS		5.0
Varity_R		0.42
gMVP		0.22
Mutation Taster		=79/21	polymorphism (auto)

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: rs1227065; hg19: chr10-73492079; COSMIC: COSV104386037;