Genetic Variant ANKRD46:p.Arg46Lys (chr8-100529697-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001270377.2(ANKRD46):c.137G>A(p.Arg46Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ANKRD46
NM_001270377.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.45

Variant links:

Genes affected

ANKRD46 (HGNC:27229): (ankyrin repeat domain 46) This gene encodes a protein containing multiple ankyrin repeats. Ankyrin domains function in protein-protein interactions in a variety of cellular processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ANKRD46 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD46	NM_001270377.2 link	c.137G>A	p.Arg46Lys	missense_variant	Exon 3 of 5	ENST00000335659.7	NP_001257306.1	Q86W74-2A0A024R9E1B3KT99
ANKRD46	NM_001270379.2 link	c.137G>A	p.Arg46Lys	missense_variant	Exon 3 of 6		NP_001257308.1	Q86W74-1A0A024R9G2
ANKRD46	NM_001270378.2 link	c.137G>A	p.Arg46Lys	missense_variant	Exon 3 of 5		NP_001257307.1	Q86W74-2A0A024R9E1
ANKRD46	NM_198401.4 link	c.137G>A	p.Arg46Lys	missense_variant	Exon 4 of 6		NP_940683.1	Q86W74-2A0A024R9E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD46	ENST00000335659.7 link	c.137G>A	p.Arg46Lys	missense_variant	Exon 3 of 5	1	NM_001270377.2	ENSP00000335287.3		Q86W74-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251350

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS 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:

0.00000205

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137G>A (p.R46K) alteration is located in exon 4 (coding exon 1) of the ANKRD46 gene. This alteration results from a G to A substitution at nucleotide position 137, causing the arginine (R) at amino acid position 46 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0055

T;.;.;.;.;T;T;T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;.;.;D;D;D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.55

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.74

N;N;N;N;.;.;.;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.6

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.13

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.18

T;T;T;T;T;T;T;.;.

Polyphen

0.92

P;P;P;P;.;.;.;.;.

Vest4

0.65

MutPred

0.50

Gain of ubiquitination at R46 (P = 0.0203);Gain of ubiquitination at R46 (P = 0.0203);Gain of ubiquitination at R46 (P = 0.0203);Gain of ubiquitination at R46 (P = 0.0203);Gain of ubiquitination at R46 (P = 0.0203);Gain of ubiquitination at R46 (P = 0.0203);Gain of ubiquitination at R46 (P = 0.0203);Gain of ubiquitination at R46 (P = 0.0203);Gain of ubiquitination at R46 (P = 0.0203);

MVP

0.82

MPC

1.0

ClinPred

0.41

GERP RS

5.8

Varity_R

0.35

gMVP

0.85

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over