10-77637551-G-C

Position:

• chr10-77637551-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001161352.2(KCNMA1):​c.92C>G​(p.Ala31Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000454 in 1,543,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNMA1. . Gene score misZ 5.0622 (greater than the threshold 3.09). Trascript score misZ 6.5162 (greater than threshold 3.09). GenCC has associacion of gene with cerebellar atrophy, developmental delay, and seizures, generalized epilepsy-paroxysmal dyskinesia syndrome, Liang-Wang syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37615994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.92C>G	p.Ala31Gly	missense_variant	1/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.92C>G	p.Ala31Gly	missense_variant	1/28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000659 AC: 1 AN: 151682 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 81084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000170

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1391378 Hom.: 0 Cov.: 29 AF XY: 0.00000145 AC XY: 1 AN XY: 687312

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: 0.00000186

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151968 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74204

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 575926). This variant has not been reported in the literature in individuals affected with KCNMA1-related conditions. This variant is present in population databases (rs201551432, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 31 of the KCNMA1 protein (p.Ala31Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0051	.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	0.016
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	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	0.93	D
MetaRNN	Benign	0.38	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	Uncertain	-0.19	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;N;N;.;N;.;.;N;N;N;.;.;N;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.26	.;.;.;.;.;N;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.29	.;.;.;.;.;T;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;T;.;.;.;.;T;T;T
Polyphen		0.030, 1.0, 0.050, 0.81, 0.12, 1.0	.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;B;P;.;.;B;.;B;.;.;.;.;D;.;.
Vest4		0.33, 0.47, 0.42, 0.32, 0.55, 0.34, 0.49, 0.54, 0.47
MutPred		0.25		Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);Gain of catalytic residue at A31 (P = 0.0102);
MVP		0.62
ClinPred		0.67	D
GERP RS		3.5
Varity_R		0.13
gMVP		0.49

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: rs201551432; hg19: chr10-79397309;