10-76877888-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The ENST00000640807.1(KCNMA1):c.3368A>G(p.Lys1123Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,457,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KCNMA1 ENST00000640807.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

KCNMA1 (HGNC:6284): (potassium calcium-activated channel subfamily M alpha 1) This gene encodes the alpha subunit of calcium-activated BK channel. The encoded protein is involved in several physiological processes including smooth muscle contraction, neurotransmitter release and neuronal excitability. Mutations in this gene are associated with a spectrum of neurological disorders including Paroxysmal Nonkinesigenic Dyskinesia 3, Idiopathic Generalized Epilepsy 16 and Liang-Wang syndrome. [provided by RefSeq, Aug 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCNMA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001322830.2	c.3620A>G	p.Lys1207Arg	missense_variant	31/31
KCNMA1	NM_001014797.3	c.3530A>G	p.Lys1177Arg	missense_variant	29/29
KCNMA1	NM_001410940.1	c.3518A>G	p.Lys1173Arg	missense_variant	28/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000640807.1	c.3368A>G	p.Lys1123Arg	missense_variant	28/28	1
KCNMA1	ENST00000604624.6	c.3113A>G	p.Lys1038Arg	missense_variant	28/28	1
KCNMA1	ENST00000639851.1	n.3739A>G		splice_region_variant, non_coding_transcript_exon_variant	30/30	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457088 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.K1207R in KCNMA1 (NM_001322830.2) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.K1207R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between lysine and arginine, which is not likely to impact secondary protein structure as these residues share similar properties. The nucleotide c.3620 in KCNMA1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Benign	-0.045
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;D;D;D;D;D;D;D;D;T;T;D;D;T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.49	T;D;D;D;D;D;D;D;D;T;T;D;D;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	0.96	D;D;D
Vest4		0.58
MVP		0.85
ClinPred		0.73	D
GERP RS		6.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200757039; hg19: chr10-78637646;