Genetic Variant NM_001242809.2:c.382A>C (chr6-89606070-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001242809.2(ANKRD6):c.382A>C(p.Ile128Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,435,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I128V) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ANKRD6
NM_001242809.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.00

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23640662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD6	NM_001242809.2 link	c.382A>C	p.Ile128Leu	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.382A>C	p.Ile128Leu	missense_variant	Exon 5 of 16	1	NM_001242809.2	ENSP00000345767.4		Q9Y2G4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1435712

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711488

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000303

AC:

AN:

33008

American (AMR)

AF:

0.00

AC:

AN:

41440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25552

East Asian (EAS)

AF:

0.00

AC:

AN:

38724

South Asian (SAS)

AF:

0.00

AC:

AN:

81506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51904

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098480

Other (OTH)

AF:

0.00

AC:

AN:

59398

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0052

.;T;.;T;T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

T;.;T;T;T;T

M_CAP

Benign

0.0097

MetaRNN

Benign

0.24

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.29

N;N;N;.;N;.

PhyloP100

4.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.94

N;N;N;N;N;N

REVEL

Benign

0.097

Sift

Benign

0.16

T;T;T;T;T;T

Sift4G

Benign

0.48

T;T;T;T;T;T

Polyphen

0.0

B;B;.;.;B;.

Vest4

0.31

MutPred

0.72

Loss of catalytic residue at I128 (P = 0.0148);Loss of catalytic residue at I128 (P = 0.0148);Loss of catalytic residue at I128 (P = 0.0148);Loss of catalytic residue at I128 (P = 0.0148);Loss of catalytic residue at I128 (P = 0.0148);Loss of catalytic residue at I128 (P = 0.0148);

MVP

0.51

MPC

0.051

ClinPred

0.34

GERP RS

4.1

Varity_R

0.088

gMVP

0.46

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over