Variant 3-183508081-A-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_130446.4(KLHL6):c.887T>G(p.Met296Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KLHL6
NM_130446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.05

Variant links:

Genes affected

KLHL6 (HGNC:18653): (kelch like family member 6) This gene encodes a member of the kelch-like (KLHL) family of proteins, which is involved in B-lymphocyte antigen receptor signaling and germinal-center B-cell maturation. The encoded protein contains an N-terminal broad-complex, tramtrack and bric a brac (BTB) domain that facilitates protein binding and dimerization, a BTB and C-terminal kelch (BACK) domain, and six C-terminal kelch repeat domains. Naturally occurring mutations in this gene are associated with chronic lymphocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

KLHL6 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=0.16092777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHL6	NM_130446.4 linkuse as main transcript	c.887T>G	p.Met296Arg	missense_variant	3/7	ENST00000341319.8	NP_569713.2
KLHL6	XM_011513273.4 linkuse as main transcript	c.506T>G	p.Met169Arg	missense_variant	2/6		XP_011511575.1
KLHL6	XM_011513274.4 linkuse as main transcript	c.887T>G	p.Met296Arg	missense_variant	3/4		XP_011511576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KLHL6	ENST00000341319.8 linkuse as main transcript	c.887T>G	p.Met296Arg	missense_variant	3/7	1	NM_130446.4	ENSP00000341342	P1
KLHL6	ENST00000489245.5 linkuse as main transcript	n.899T>G		non_coding_transcript_exon_variant	3/4	1
KLHL6	ENST00000468734.1 linkuse as main transcript	c.854T>G	p.Met285Arg	missense_variant, NMD_transcript_variant	3/8	1		ENSP00000433734

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251054

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

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:

6.84e-7

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.887T>G (p.M296R) alteration is located in exon 3 (coding exon 3) of the KLHL6 gene. This alteration results from a T to G substitution at nucleotide position 887, causing the methionine (M) at amino acid position 296 to be replaced by an arginine (R). 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

0.19

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.033

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.66

M_CAP

Benign

0.0070

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.90

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.28

REVEL

Benign

0.12

Sift

Benign

0.63

Sift4G

Benign

0.75

Polyphen

0.0

Vest4

0.35

MutPred

0.54

Gain of catalytic residue at M296 (P = 0.0067);

MVP

0.75

MPC

0.29

ClinPred

0.20

GERP RS

5.2

Varity_R

0.46

gMVP

0.63

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