Variant 1-62274428-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_181712.5(KANK4):c.676G>C(p.Glu226Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

KANK4
NM_181712.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.347

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:

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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=0.060850352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANK4	NM_181712.5 linkuse as main transcript	c.676G>C	p.Glu226Gln	missense_variant	3/10	ENST00000371153.9	NP_859063.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANK4	ENST00000371153.9 linkuse as main transcript	c.676G>C	p.Glu226Gln	missense_variant	3/10	1	NM_181712.5	ENSP00000360195	P1	Q5T7N3-1
KANK4	ENST00000354381.3 linkuse as main transcript	c.17-2839G>C		intron_variant		2		ENSP00000346352		Q5T7N3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251364

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.0000239

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 09, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 226 of the KANK4 protein (p.Glu226Gln). This variant is present in population databases (rs757119605, gnomAD 0.1%), 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.9

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0051

Eigen

Benign

0.057

Eigen_PC

Benign

-0.076

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.57

M_CAP

Benign

0.017

MetaRNN

Benign

0.061

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.99

D;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.0

REVEL

Benign

0.26

Sift

Uncertain

0.010

Sift4G

Benign

0.068

Polyphen

0.99

Vest4

0.25

MutPred

0.11

Gain of helix (P = 0.062);

MVP

0.71

MPC

0.094

ClinPred

0.18

GERP RS

4.5

Varity_R

0.11

gMVP

0.13

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