19-4199764-C-T

Variant names:

• chr19-4199764-C-T
• rs60004310
• NM_001393985.1:c.118C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001393985.1(ANKRD24):​c.118C>T​(p.Arg40Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000976 in 1,536,780 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: ANKRD24 NM_001393985.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.267
• Publications: 0 publications found

Genes affected

ANKRD24 (HGNC:29424): (ankyrin repeat domain 24)

ANKRD24 Gene-Disease associations (from GenCC):

• sensorineural hearing loss disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000306086 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043598473).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393985.1. 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
	ANKRD24	NM_001393985.1	MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 3 of 22	NP_001380914.1	Q8TF21-1
	ANKRD24	NM_001393552.1		c.118C>T	p.Arg40Cys	missense	Exon 3 of 23	NP_001380481.1
	ANKRD24	NM_001393553.1		c.118C>T	p.Arg40Cys	missense	Exon 3 of 22	NP_001380482.1	Q8TF21-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD24	ENST00000318934.9	TSL:5 MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 3 of 22	ENSP00000321731.4	Q8TF21-1
	ANKRD24	ENST00000597689.5	TSL:1	c.37-111C>T		intron	N/A	ENSP00000470227.1	M0QZ18
	ANKRD24	ENST00000966466.1		c.118C>T	p.Arg40Cys	missense	Exon 3 of 23	ENSP00000636525.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000224 AC: 3 AN: 134146 AF XY: 0.0000274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000951

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000722 AC: 10 AN: 1384456 Hom.: 0 Cov.: 30 AF XY: 0.00000586 AC XY: 4 AN XY: 682596

African (AFR) AF: 0.00 AC: 0 AN: 31458

American (AMR) AF: 0.00 AC: 0 AN: 35232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24950

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35642

South Asian (SAS) AF: 0.0000254 AC: 2 AN: 78810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5104

European-Non Finnish (NFE) AF: 0.00000372 AC: 4 AN: 1075830

Other (OTH) AF: 0.0000521 AC: 3 AN: 57556

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000217 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.27
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.022
Sift	Benign	0.24	T
Sift4G	Benign	0.21	T
Polyphen		0.013	B
Vest4		0.20
MutPred		0.36		Loss of MoRF binding (P = 0.0056)
MVP		0.099
MPC		0.35
ClinPred		0.062	T
GERP RS		0.82
Varity_R		0.066
gMVP		0.44
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs60004310; hg19: chr19-4199761; COSMIC: COSV53669716;