Genetic Variant KLHL6:p.Ala524Ser (chr3-183492223-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_130446.4(KLHL6):c.1570G>T(p.Ala524Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,444,528 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: 0.0000021 ( 0 hom. )

Consequence

KLHL6
NM_130446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL6	NM_130446.4 link	c.1570G>T	p.Ala524Ser	missense_variant	Exon 7 of 7	ENST00000341319.8	NP_569713.2	Q8WZ60
KLHL6	XM_011513273.4 link	c.1189G>T	p.Ala397Ser	missense_variant	Exon 6 of 6		XP_011511575.1
KLHL6	XM_011513274.4 link	c.*1984G>T		3_prime_UTR_variant	Exon 4 of 4		XP_011511576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHL6	ENST00000341319.8 link	c.1570G>T	p.Ala524Ser	missense_variant	Exon 7 of 7	1	NM_130446.4	ENSP00000341342.3	Q8WZ60
KLHL6	ENST00000468734.1 link	n.1537G>T		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000433734.1	A0A0C4DGF2
KLHL6	ENST00000489245.5 link	n.2980G>T		non_coding_transcript_exon_variant	Exon 4 of 4	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000426

AC:

AN:

234904

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1444528

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33134

American (AMR)

AF:

0.00

AC:

AN:

43328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25256

East Asian (EAS)

AF:

0.00

AC:

AN:

39366

South Asian (SAS)

AF:

0.00

AC:

AN:

84710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101438

Other (OTH)

AF:

0.0000504

AC:

AN:

59496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1570G>T (p.A524S) alteration is located in exon 7 (coding exon 7) of the KLHL6 gene. This alteration results from a G to T substitution at nucleotide position 1570, causing the alanine (A) at amino acid position 524 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

Benign

0.29

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.73

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.5

PhyloP100

7.4

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.33

REVEL

Benign

0.25

Sift

Benign

0.45

Sift4G

Benign

0.48

Polyphen

0.61

Vest4

0.59

MutPred

0.49

Gain of sheet (P = 0.0827);

MVP

0.76

MPC

2.0

ClinPred

0.66

GERP RS

5.5

Varity_R

0.061

gMVP

0.50

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over