Variant 3-183491961-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_130446.4(KLHL6):c.1832T>G(p.Ile611Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,392,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

KLHL6
NM_130446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.58

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHL6	NM_130446.4 linkuse as main transcript	c.1832T>G	p.Ile611Ser	missense_variant	7/7	ENST00000341319.8	NP_569713.2
KLHL6	XM_011513273.4 linkuse as main transcript	c.1451T>G	p.Ile484Ser	missense_variant	6/6		XP_011511575.1
KLHL6	XM_011513274.4 linkuse as main transcript	c.*2246T>G		3_prime_UTR_variant	4/4		XP_011511576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KLHL6	ENST00000341319.8 linkuse as main transcript	c.1832T>G	p.Ile611Ser	missense_variant	7/7	1	NM_130446.4	ENSP00000341342	P1
KLHL6	ENST00000489245.5 linkuse as main transcript	n.3242T>G		non_coding_transcript_exon_variant	4/4	1
KLHL6	ENST00000468734.1 linkuse as main transcript	c.1799T>G	p.Ile600Ser	missense_variant, NMD_transcript_variant	7/8	1		ENSP00000433734

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000480

AC:

AN:

208322

Hom.:

AF XY:

0.00

AC XY:

AN XY:

112914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000650

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:

0.00000215

AC:

AN:

1392234

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

687132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000801

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.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

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

May 30, 2024

The c.1832T>G (p.I611S) alteration is located in exon 7 (coding exon 7) of the KLHL6 gene. This alteration results from a T to G substitution at nucleotide position 1832, causing the isoleucine (I) at amino acid position 611 to be replaced by a serine (S). 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

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

0.069

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.81

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

0.24

Vest4

0.69

MutPred

0.70

Gain of disorder (P = 0.0023);

MVP

0.83

MPC

2.4

ClinPred

0.63

GERP RS

5.7

Varity_R

0.48

gMVP

0.99

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