chr8-100529697-C-T

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

2
9
8

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]

Genome browser will be placed here

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
ANKRD46NM_001270377.2 linkc.137G>A p.Arg46Lys missense_variant Exon 3 of 5 ENST00000335659.7 NP_001257306.1 Q86W74-2A0A024R9E1B3KT99
ANKRD46NM_001270379.2 linkc.137G>A p.Arg46Lys missense_variant Exon 3 of 6 NP_001257308.1 Q86W74-1A0A024R9G2
ANKRD46NM_001270378.2 linkc.137G>A p.Arg46Lys missense_variant Exon 3 of 5 NP_001257307.1 Q86W74-2A0A024R9E1
ANKRD46NM_198401.4 linkc.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
ANKRD46ENST00000335659.7 linkc.137G>A p.Arg46Lys missense_variant Exon 3 of 5 1 NM_001270377.2 ENSP00000335287.3 Q86W74-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251350
Hom.:
0
AF XY:
0.00000736
AC XY:
1
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:
3
AN:
1461894
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
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.:
32
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

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
T
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
25
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
D
LIST_S2
Uncertain
0.88
D;.;.;D;D;D;D;D;D
M_CAP
Benign
0.017
T
MetaRNN
Uncertain
0.55
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
0.74
N;N;N;N;.;.;.;.;.
PrimateAI
Pathogenic
0.87
D
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
T
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.

Other links and lift over

dbSNP: rs769104118; hg19: chr8-101541925; API