chr2-10913756-G-A

Position:

• chr2-10913756-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002236.5(KCNF1):​c.1330G>A​(p.Gly444Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNF1 NM_002236.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.804

Genes affected

KCNF1 (HGNC:6246): (potassium voltage-gated channel modifier subfamily F member 1) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily F. This gene is intronless and expressed in all tissues tested, including the heart, skeletal muscle, brain, kidney, and pancreas. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06297204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNF1	NM_002236.5	c.1330G>A	p.Gly444Ser	missense_variant	1/1	ENST00000295082.3	NP_002227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNF1	ENST00000295082.3	c.1330G>A	p.Gly444Ser	missense_variant	1/1		NM_002236.5	ENSP00000295082	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Aug 22, 2023

The c.1330G>A (p.G444S) alteration is located in exon 1 (coding exon 1) of the KCNF1 gene. This alteration results from a G to A substitution at nucleotide position 1330, causing the glycine (G) at amino acid position 444 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	0.074
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.063	T
MetaSVM	Uncertain	0.011	D
MutationAssessor	Benign	-0.46	N
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.25
Sift	Benign	0.52	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.090
MutPred		0.16		Gain of phosphorylation at G444 (P = 0.0043);
MVP		0.88
MPC		1.1
ClinPred		0.048	T
GERP RS		2.8
Varity_R		0.040
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs756330748; hg19: chr2-11053882;