ENST00000469435.1:c.704C>G

Variant names:

• chr10-3781613-G-C
• rs192712828
• ENST00000469435.1:c.704C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The ENST00000469435.1(KLF6):​c.704C>G​(p.Ala235Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A235V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KLF6 ENST00000469435.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -7 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=0.06316581).
• BS2: High AC in GnomAdExome4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF6	NM_001300.6	MANE Select	c.676+28C>G		intron	N/A	NP_001291.3
	KLF6	NM_001160124.2		c.550+154C>G		intron	N/A	NP_001153596.1
	KLF6	NM_001160125.2		c.676+28C>G		intron	N/A	NP_001153597.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF6	ENST00000469435.1	TSL:1	c.704C>G	p.Ala235Gly	missense	Exon 2 of 2	ENSP00000419079.1
	KLF6	ENST00000497571.6	TSL:1 MANE Select	c.676+28C>G		intron	N/A	ENSP00000419923.1
	KLF6	ENST00000542957.1	TSL:5	c.676+28C>G		intron	N/A	ENSP00000445301.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1456828 Hom.: 0 Cov.: 32 AF XY: 0.00000552 AC XY: 4 AN XY: 724446

African (AFR) AF: 0.00 AC: 0 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109786

Other (OTH) AF: 0.0000166 AC: 1 AN: 60086

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.5
DANN	Uncertain	0.99
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.046
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.047
Sift	Benign	0.23	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.14
MutPred		0.23		Loss of stability (P = 0.1048)
MVP		0.47
ClinPred		0.053	T
GERP RS		-1.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs192712828; hg19: chr10-3823805;