10-76949286-G-C

Variant names:

• chr10-76949286-G-C
• rs2229009
• NM_001161352.2:c.2565C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001161352.2(KCNMA1):​c.2565C>G​(p.Ile855Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I855I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.855
• 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-AS1 (HGNC:51213): (KCNMA1 antisense RNA 1)

LOC124902466 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33332676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.2565C>G	p.Ile855Met	missense_variant	Exon 22 of 28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.2565C>G	p.Ile855Met	missense_variant	Exon 22 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

⚠️ 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: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T;T;T;D;D;T;D;D;D;D;D;T;T;D;D;D;D;D;T;D;T;D;D;D;D;D;T;D;D;D;D;D;T;.;T;D;D;D;D;D;T;D;D;D;D;D;D;D;D;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		0.85
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.14	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.13	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;T;T;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		0.93, 0.27, 0.94, 0.17	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;B;P;.;.;.;.;.;.;P;B;.;.;B;.;.;.
Vest4		0.51, 0.54, 0.51, 0.54, 0.47, 0.60
MutPred		0.33		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of catalytic residue at I855 (P = 0.0056);Loss of catalytic residue at I855 (P = 0.0056);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of catalytic residue at I855 (P = 0.0056);.;.;.;Loss of catalytic residue at I855 (P = 0.0056);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.90
MPC		2.3
ClinPred		0.80	D
GERP RS		0.77
Varity_R		0.19
gMVP		0.66
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs2229009; hg19: chr10-78709044; COSMIC: COSV54252972;