Genetic Variant ANKRD6:p.Arg43Leu (chr6-89595923-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001242809.2(ANKRD6):c.128G>T(p.Arg43Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R43Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ANKRD6
NM_001242809.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.36

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.774

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANKRD6	NM_001242809.2	MANE Select	c.128G>T	p.Arg43Leu	missense	Exon 3 of 16	NP_001229738.1	Q9Y2G4-2
ANKRD6	NM_001242811.1		c.128G>T	p.Arg43Leu	missense	Exon 3 of 16	NP_001229740.1	Q9Y2G4-2
ANKRD6	NM_014942.4		c.128G>T	p.Arg43Leu	missense	Exon 3 of 16	NP_055757.3	Q9Y2G4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANKRD6	ENST00000339746.9	TSL:1 MANE Select	c.128G>T	p.Arg43Leu	missense	Exon 3 of 16	ENSP00000345767.4	Q9Y2G4-2
ANKRD6	ENST00000447838.6	TSL:1	c.128G>T	p.Arg43Leu	missense	Exon 3 of 16	ENSP00000396771.2	Q9Y2G4-3
ANKRD6	ENST00000369408.9	TSL:1	c.128G>T	p.Arg43Leu	missense	Exon 3 of 15	ENSP00000358416.5	Q9Y2G4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454968

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722912

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

43904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25924

East Asian (EAS)

AF:

0.00

AC:

AN:

39542

South Asian (SAS)

AF:

0.00

AC:

AN:

84420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108870

Other (OTH)

AF:

0.00

AC:

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.1

PhyloP100

9.4

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.68

Sift

Benign

0.055

Sift4G

Benign

0.070

Polyphen

1.0

Vest4

0.92

MutPred

0.60

Loss of MoRF binding (P = 0.0092)

MVP

0.84

MPC

0.37

ClinPred

0.99

GERP RS

5.8

Varity_R

0.36

gMVP

0.76

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over