1-62238335-A-T

Position:

chr1-62238335-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_181712.5(KANK4):c.2930T>A(p.Met977Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,613,914 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

KANK4
NM_181712.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.104

Variant links:

Genes affected

KANK4 (HGNC:27263): (KN motif and ankyrin repeat domains 4) Predicted to be involved in negative regulation of actin filament polymerization. Located in cytosol and microtubule cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

KANK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0065174103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANK4	NM_181712.5 linkuse as main transcript	c.2930T>A	p.Met977Lys	missense_variant	10/10	ENST00000371153.9	NP_859063.3	Q5T7N3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KANK4	ENST00000371153.9 linkuse as main transcript	c.2930T>A	p.Met977Lys	missense_variant	10/10	1	NM_181712.5	ENSP00000360195.4	Q5T7N3-1
KANK4	ENST00000354381.3 linkuse as main transcript	c.1046T>A	p.Met349Lys	missense_variant	9/9	2		ENSP00000346352.3	Q5T7N3-2
KANK4	ENST00000371150.5 linkuse as main transcript	c.998T>A	p.Met333Lys	missense_variant	7/7	2		ENSP00000360192.1	B1ALP6
KANK4	ENST00000317477.8 linkuse as main transcript	c.344T>A	p.Met115Lys	missense_variant	4/4	2		ENSP00000321161.4	B1ALP5

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000335

AC:

AN:

250834

Hom.:

AF XY:

0.000332

AC XY:

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.000601

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000270

AC:

395

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

231

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.000323

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000322

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000419

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2024

The c.2930T>A (p.M977K) alteration is located in exon 10 (coding exon 9) of the KANK4 gene. This alteration results from a T to A substitution at nucleotide position 2930, causing the methionine (M) at amino acid position 977 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 977 of the KANK4 protein (p.Met977Lys). This variant is present in population databases (rs145877699, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KANK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1524284). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

KANK4-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2022

The KANK4 c.2930T>A variant is predicted to result in the amino acid substitution p.Met977Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-62704007-A-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.7

DANN

Benign

0.84

DEOGEN2

Benign

0.0028

T;T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.44

T;T;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.0065

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.0

.;N;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

0.050

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.95

T;T;T;T

Polyphen

0.0010

.;B;.;B

Vest4

0.087

MVP

0.11

MPC

0.15

ClinPred

0.023

GERP RS

2.7

Varity_R

0.26

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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