10-76877888-T-C

Variant names:

• chr10-76877888-T-C
• rs200757039
• ENST00000640807.1:c.3368A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

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
• Publications: 0 publications found

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]

KCNMA1 Gene-Disease associations (from GenCC):

• generalized epilepsy-paroxysmal dyskinesia syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• Liang-Wang syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• cerebellar atrophy, developmental delay, and seizures

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001322830.2	c.3620A>G	p.Lys1207Arg	missense_variant	Exon 31 of 31		NP_001309759.1
KCNMA1	NM_001437423.1	c.3605A>G	p.Lys1202Arg	missense_variant	Exon 29 of 29		NP_001424352.1
KCNMA1	NM_001014797.3	c.3530A>G	p.Lys1177Arg	missense_variant	Exon 29 of 29		NP_001014797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000640807.1	c.3368A>G	p.Lys1123Arg	missense_variant	Exon 28 of 28	1		ENSP00000491555.1
KCNMA1	ENST00000604624.6	c.3113A>G	p.Lys1038Arg	missense_variant	Exon 28 of 28	1		ENSP00000473714.2
KCNMA1	ENST00000639691.1	n.*2394A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 25	1		ENSP00000491040.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44154

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 84828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109798

Other (OTH) AF: 0.0000166 AC: 1 AN: 60250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000010), which strongly suggests a high chance of mosaicism in these individuals.

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

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.010	.;.;.;.;T;.;.;.;.;.;.;.;.;.
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
PhyloP100		7.7
REVEL	Uncertain	0.41
Sift4G	Uncertain	0.021	.;.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.58
MVP		0.85
ClinPred		0.73	D
GERP RS		6.0
Mutation Taster		=55/45	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs200757039; hg19: chr10-78637646;