dbSNP rs186624120: KLF6:p.Ala246Val (chr10-3781580-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The ENST00000469435.1(KLF6):c.737C>T(p.Ala246Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000892 in 1,599,390 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.0049 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00047 ( 14 hom. )

Consequence

KLF6
ENST00000469435.1 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 1.96

Publications

1 publications found

Variant links:

Genes affected

KLF6 (HGNC:2235): (KLF transcription factor 6) This gene encodes a member of the Kruppel-like family of transcription factors. The zinc finger protein is a transcriptional activator, and functions as a tumor suppressor. Multiple transcript variants encoding different isoforms have been found for this gene, some of which are implicated in carcinogenesis. [provided by RefSeq, May 2009]

KLF6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.8535 (below the threshold of 3.09). Trascript score misZ: 1.628 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.004200399).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00491 (748/152356) while in subpopulation AFR AF = 0.0171 (711/41594). AF 95% confidence interval is 0.0161. There are 4 homozygotes in GnomAd4. There are 366 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 748 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000469435.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KLF6	NM_001300.6	MANE Select	c.676+61C>T	intron	N/A	NP_001291.3
KLF6	NM_001160124.2		c.550+187C>T	intron	N/A	NP_001153596.1
KLF6	NM_001160125.2		c.676+61C>T	intron	N/A	NP_001153597.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KLF6	ENST00000469435.1	TSL:1	c.737C>T	p.Ala246Val	missense	Exon 2 of 2	ENSP00000419079.1
KLF6	ENST00000497571.6	TSL:1 MANE Select	c.676+61C>T		intron	N/A	ENSP00000419923.1
KLF6	ENST00000542957.1	TSL:5	c.676+61C>T		intron	N/A	ENSP00000445301.1

Frequencies

GnomAD3 genomes

AF:

0.00491

AC:

747

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00106

AC:

230

AN:

216630

AF XY:

0.000827

show subpopulations

Gnomad AFR exome

AF:

0.0168

Gnomad AMR exome

AF:

0.000608

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000321

Gnomad OTH exome

AF:

0.000181

GnomAD4 exome

AF:

0.000469

AC:

679

AN:

1447034

Hom.:

Cov.:

AF XY:

0.000383

AC XY:

275

AN XY:

718872

show subpopulations

African (AFR)

AF:

0.0170

AC:

561

AN:

33068

American (AMR)

AF:

0.000644

AC:

AN:

41922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25838

East Asian (EAS)

AF:

0.00

AC:

AN:

38684

South Asian (SAS)

AF:

0.00

AC:

AN:

84786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52192

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000145

AC:

AN:

1104954

Other (OTH)

AF:

0.00122

AC:

AN:

59840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

133

177

221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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

AF:

0.00491

AC:

748

AN:

152356

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

366

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0171

AC:

711

AN:

41594

American (AMR)

AF:

0.00189

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00275

Hom.:

Bravo

AF:

0.00526

ExAC

AF:

0.00143

AC:

171

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.0

PhyloP100

2.0

PROVEAN

Benign

-0.52

REVEL

Benign

0.042

Sift

Uncertain

0.011

Sift4G

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.12

MVP

0.44

ClinPred

0.015

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over