Genetic Variant NM_001242809.2:c.403C>G (chr6-89606091-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001242809.2(ANKRD6):c.403C>G(p.Leu135Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000563 in 1,420,656 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000056 ( 1 hom. )

Consequence

ANKRD6
NM_001242809.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.85

Variant links:

Genes affected

ANKRD6 (HGNC:17280): (ankyrin repeat domain 6) Predicted to be involved in negative regulation of canonical Wnt signaling pathway and positive regulation of JNK cascade. Predicted to act upstream of or within positive regulation of Wnt signaling pathway, planar cell polarity pathway. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ANKRD6 links:

LYRM2 (HGNC:25229): (LYR motif containing 2)

LYRM2 links:

LOC124901359 (HGNC:):

LOC124901359 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16495931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD6	NM_001242809.2 link	c.403C>G	p.Leu135Val	missense_variant	Exon 5 of 16	ENST00000339746.9	NP_001229738.1	Q9Y2G4-2B7Z3D2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD6	ENST00000339746.9 link	c.403C>G	p.Leu135Val	missense_variant	Exon 5 of 16	1	NM_001242809.2	ENSP00000345767.4		Q9Y2G4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000936

AC:

AN:

192306

Hom.:

AF XY:

0.000146

AC XY:

AN XY:

102516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000701

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000198

GnomAD4 exome

AF:

0.0000563

AC:

AN:

1420656

Hom.:

Cov.:

AF XY:

0.0000768

AC XY:

AN XY:

702960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000862

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.17e-7

Gnomad4 OTH exome

AF:

0.000170

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000832

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.403C>G (p.L135V) alteration is located in exon 5 (coding exon 4) of the ANKRD6 gene. This alteration results from a C to G substitution at nucleotide position 403, causing the leucine (L) at amino acid position 135 to be replaced by a valine (V). 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

Benign

0.16

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0077

.;T;.;T;T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;.;D;D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.16

T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.5

L;L;L;.;L;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.070

N;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.52

T;T;T;T;T;T

Sift4G

Benign

0.29

T;T;T;T;T;T

Polyphen

0.78

P;D;.;.;D;.

Vest4

0.42

MutPred

0.51

Loss of ubiquitination at K137 (P = 0.0931);Loss of ubiquitination at K137 (P = 0.0931);Loss of ubiquitination at K137 (P = 0.0931);Loss of ubiquitination at K137 (P = 0.0931);Loss of ubiquitination at K137 (P = 0.0931);Loss of ubiquitination at K137 (P = 0.0931);

MVP

0.59

MPC

0.17

ClinPred

0.23

GERP RS

5.0

Varity_R

0.10

gMVP

0.21

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