10-77637553-G-C

Variant names:

• chr10-77637553-G-C
• rs75040504
• NM_001161352.2:c.90C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001161352.2(KCNMA1):​c.90C>G​(p.His30Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000719 in 1,391,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. H30H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.02

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCNMA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 5.0622 (above the threshold of 3.09). Trascript score misZ: 6.5162 (above the threshold of 3.09). GenCC associations: The gene is linked to cerebellar atrophy, developmental delay, and seizures, generalized epilepsy-paroxysmal dyskinesia syndrome, Liang-Wang syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33093584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.90C>G	p.His30Gln	missense_variant	Exon 1 of 28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.90C>G	p.His30Gln	missense_variant	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391296 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 687120

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: 9.30e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.0074	.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.0037
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
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
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;N;N;.;N;.;.;N;N;N;.;.;N;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.37	.;.;.;.;.;N;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0030	.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.063	.;.;.;.;.;T;.;.;.;.;.;D;.;T;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;T;.;.;.;.;T;T;T
Polyphen		0.0, 0.031, 0.94, 0.14	.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;B;.;B;P;.;.;B;.;B;.;.;.;.;B;.;.
Vest4		0.25, 0.34, 0.32, 0.23, 0.33, 0.23, 0.34, 0.36, 0.33
MutPred		0.22		Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);Gain of MoRF binding (P = 0.0854);
MVP		0.64
ClinPred		0.62	D
GERP RS		2.6
Varity_R		0.13
gMVP		0.35

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: rs75040504; hg19: chr10-79397311;