NM_022124.6:c.3361A>T

Variant names:

• chr10-71712805-A-T
• rs200542052
• NM_022124.6:c.3361A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_022124.6(CDH23):​c.3361A>T​(p.Ile1121Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000238 in 1,612,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. I1121V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 6.27
• Publications: 6 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013111502).
• BP6: Variant 10-71712805-A-T is Benign according to our data. Variant chr10-71712805-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45916.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00129 (196/152374) while in subpopulation AFR AF = 0.0045 (187/41600). AF 95% confidence interval is 0.00397. There are 0 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.3361A>T	p.Ile1121Phe	missense	Exon 28 of 70	NP_071407.4
	C10orf105	NM_001164375.3	MANE Select	c.*3131T>A		3_prime_UTR	Exon 2 of 2	NP_001157847.1	Q8TEF2
	CDH23	NM_001171930.2		c.3361A>T	p.Ile1121Phe	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.3361A>T	p.Ile1121Phe	missense	Exon 28 of 70	ENSP00000224721.9	Q9H251-1
	C10orf105	ENST00000441508.4	TSL:1 MANE Select	c.*3131T>A		3_prime_UTR	Exon 2 of 2	ENSP00000403151.2	Q8TEF2
	CDH23	ENST00000616684.4	TSL:5	c.3361A>T	p.Ile1121Phe	missense	Exon 28 of 32	ENSP00000482036.2	A0A087WYR8

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000332 AC: 81 AN: 243680 AF XY: 0.000218

Gnomad AFR exome AF: 0.00494

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1459744 Hom.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 725998

African (AFR) AF: 0.00445 AC: 149 AN: 33458

American (AMR) AF: 0.000247 AC: 11 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52842

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111342

Other (OTH) AF: 0.000365 AC: 22 AN: 60302

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.00125 AC XY: 93 AN XY: 74522

African (AFR) AF: 0.00450 AC: 187 AN: 41600

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.00151

ESP6500AA AF: 0.00416 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000397 AC: 48

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	not specified (1)
-	1	-	Retinal dystrophy (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.3
PrimateAI	Uncertain	0.52	T
REVEL	Uncertain	0.31
Sift4G	Uncertain	0.0030	D
Polyphen		0.85	P
Vest4		0.93
MVP		0.88
ClinPred		0.092	T
GERP RS		4.9
Varity_R		0.34
gMVP		0.73
Mutation Taster		=55/45	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: rs200542052; hg19: chr10-73472562;