rs1227051

Variant names:

• chr10-71741799-G-A
• rs1227051
• NM_022124.6:c.4723G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71741799-G-A
• chr10-71741799-G-C

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.4723G>A​(p.Ala1575Thr) variant causes a missense change. The variant allele was found at a frequency of 0.771 in 1,611,736 control chromosomes in the GnomAD database, including 481,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1575A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.73 (41484 hom., cov: 33)
  • Exomes 𝑓: 0.78 (439521 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 6.19
• Publications: 54 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.691493E-6).
• BP6: Variant 10-71741799-G-A is Benign according to our data. Variant chr10-71741799-G-A is described in ClinVar as Benign. ClinVar VariationId is 45955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 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.4723G>A	p.Ala1575Thr	missense	Exon 38 of 70	NP_071407.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.4723G>A	p.Ala1575Thr	missense	Exon 38 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000398792.3	TSL:2	n.1412G>A		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111674 AN: 152044 Hom.: 41460 Cov.: 33

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.745

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.859

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.786

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.761

GnomAD2 exomes AF: 0.774 AC: 189554 AN: 244850 AF XY: 0.777

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.776

Gnomad ASJ exome AF: 0.850

Gnomad EAS exome AF: 0.832

Gnomad FIN exome AF: 0.746

Gnomad NFE exome AF: 0.782

Gnomad OTH exome AF: 0.789

GnomAD4 exome AF: 0.775 AC: 1131293 AN: 1459574 Hom.: 439521 Cov.: 67 AF XY: 0.776 AC XY: 563594 AN XY: 725860

African (AFR) AF: 0.595 AC: 19911 AN: 33444

American (AMR) AF: 0.770 AC: 34192 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.853 AC: 22222 AN: 26040

East Asian (EAS) AF: 0.824 AC: 32663 AN: 39654

South Asian (SAS) AF: 0.785 AC: 67425 AN: 85900

European-Finnish (FIN) AF: 0.747 AC: 39650 AN: 53060

Middle Eastern (MID) AF: 0.788 AC: 4543 AN: 5766

European-Non Finnish (NFE) AF: 0.778 AC: 864213 AN: 1111002

Other (OTH) AF: 0.771 AC: 46474 AN: 60296

GnomAD4 genome AF: 0.734 AC: 111743 AN: 152162 Hom.: 41484 Cov.: 33 AF XY: 0.734 AC XY: 54617 AN XY: 74380

African (AFR) AF: 0.611 AC: 25378 AN: 41524

American (AMR) AF: 0.769 AC: 11773 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.859 AC: 2982 AN: 3470

East Asian (EAS) AF: 0.821 AC: 4231 AN: 5154

South Asian (SAS) AF: 0.788 AC: 3799 AN: 4824

European-Finnish (FIN) AF: 0.747 AC: 7914 AN: 10598

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53163 AN: 67972

Other (OTH) AF: 0.763 AC: 1612 AN: 2112

Alfa AF: 0.774 Hom.: 213320

Bravo AF: 0.734

TwinsUK AF: 0.785 AC: 2909

ALSPAC AF: 0.779 AC: 3004

ESP6500AA AF: 0.634 AC: 2783

ESP6500EA AF: 0.796 AC: 6814

ExAC AF: 0.767 AC: 92912

Asia WGS AF: 0.780 AC: 2712 AN: 3478

EpiCase AF: 0.794

EpiControl AF: 0.790

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	0.054
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.75
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N
PhyloP100		6.2
PrimateAI	Benign	0.42	T
REVEL	Benign	0.10
Sift4G	Benign	1.0	T
Vest4		0.082
ClinPred		0.0096	T
GERP RS		5.1
Varity_R		0.17
gMVP		0.12
Mutation Taster		=90/10	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: rs1227051; hg19: chr10-73501556; COSMIC: COSV56490242; COSMIC: COSV56490242;