3-183492018-A-C

Position:

• chr3-183492018-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_130446.4(KLHL6):​c.1775T>G​(p.Leu592Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL6 NM_130446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.10

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL6	NM_130446.4	c.1775T>G	p.Leu592Arg	missense_variant	7/7	ENST00000341319.8	NP_569713.2
KLHL6	XM_011513273.4	c.1394T>G	p.Leu465Arg	missense_variant	6/6		XP_011511575.1
KLHL6	XM_011513274.4	c.*2189T>G		3_prime_UTR_variant	4/4		XP_011511576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL6	ENST00000341319.8	c.1775T>G	p.Leu592Arg	missense_variant	7/7	1	NM_130446.4	ENSP00000341342.3
KLHL6	ENST00000468734.1	n.1742T>G		non_coding_transcript_exon_variant	7/8	1		ENSP00000433734.1
KLHL6	ENST00000489245.5	n.3185T>G		non_coding_transcript_exon_variant	4/4	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.1775T>G (p.L592R) 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 1775, causing the leucine (L) at amino acid position 592 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.89		Gain of disorder (P = 0.0218);
MVP		0.84
MPC		2.7
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.76
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-183209806;