2-85049531-G-A

Position:

• chr2-85049531-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020122.5(KCMF1):​c.767G>A​(p.Arg256Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,708 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: 0.0000055 (0 hom.)
• Consequence: KCMF1 NM_020122.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.61

Genes affected

KCMF1 (HGNC:20589): (potassium channel modulatory factor 1) Enables ubiquitin protein ligase activity. Predicted to be involved in synaptic signaling. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCMF1	NM_020122.5	c.767G>A	p.Arg256Gln	missense_variant	6/7	ENST00000409785.9	NP_064507.3
KCMF1	XM_006712052.4	c.791G>A	p.Arg264Gln	missense_variant	6/7		XP_006712115.1
KCMF1	XM_047445126.1	c.614G>A	p.Arg205Gln	missense_variant	7/8		XP_047301082.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCMF1	ENST00000409785.9	c.767G>A	p.Arg256Gln	missense_variant	6/7	1	NM_020122.5	ENSP00000386738.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000224 Hom.: 0

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

Feb 28, 2024

The c.767G>A (p.R256Q) alteration is located in exon 6 (coding exon 6) of the KCMF1 gene. This alteration results from a G to A substitution at nucleotide position 767, causing the arginine (R) at amino acid position 256 to be replaced by a glutamine (Q). 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	0.097
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.21
Sift	Benign	0.15	T
Sift4G	Benign	0.63	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.10		Loss of methylation at R256 (P = 0.0507);
MVP		0.31
MPC		1.1
ClinPred		0.72	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.36

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: rs1195349486; hg19: chr2-85276654;