chr10-3780231-T-C

Variant names:

• chr10-3780231-T-C
• rs2131095903
• ENST00000492125.1:n.266A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001300.6(KLF6):​c.677-2A>G variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain_significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLF6 NM_001300.6 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: - - O:1
• Conservation: PhyloP100: 7.90
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.3, offset of -38, new splice context is: cctttccgtctgcgggtcAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF6	NM_001300.6	c.677-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 3	ENST00000497571.6	NP_001291.3
KLF6	NM_001160124.2	c.551-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 3		NP_001153596.1
KLF6	NM_001160125.2	c.677-641A>G		intron_variant	Intron 2 of 2		NP_001153597.1
KLF6	NR_027653.2	n.718-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF6	ENST00000497571.6	c.677-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 3	1	NM_001300.6	ENSP00000419923.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

not provided Other:1

-

MutSpliceDB: a database of splice sites variants effects on splicing, NIH

Significance: not provided

Review Status: no classification provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		7.9
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2131095903; hg19: chr10-3822423; COSMIC: COSV99434953; COSMIC: COSV99434953;