rs369845234

chr10-77637558-T-Achr10-77637558-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Moderate BP6_Moderate

The NM_001161352.2(KCNMA1):c.85A>T(p.Ile29Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,542,920 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I29V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (1 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.79

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCNMA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.2519365).
• BP6: Variant 10-77637558-T-A is Benign according to our data. Variant chr10-77637558-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2905605.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.85A>T	p.Ile29Phe	missense_variant	1/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.85A>T	p.Ile29Phe	missense_variant	1/28	1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000879 AC: 13 AN: 147822 Hom.: 1 AF XY: 0.0000885 AC XY: 7 AN XY: 79124

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: 0.000571

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000316 AC: 44 AN: 1390974 Hom.: 1 Cov.: 30 AF XY: 0.0000422 AC XY: 29 AN XY: 686688

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: 0.000529

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151946 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000777 AC: 8

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	0.086
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	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	0.77	D
MetaRNN	Benign	0.25	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	-0.95	T
MutationTaster	Benign	0.51	D;D;D;D;D;D
PrimateAI	Pathogenic	0.95	D
Polyphen		0.072, 0.98, 0.12, 0.85, 0.26, 0.99	.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;B;P;.;.;B;.;B;.;.;.;.;D;.;.
Vest4		0.61, 0.72, 0.65, 0.53, 0.69, 0.49, 0.72, 0.78, 0.76
MutPred		0.21		Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);Loss of catalytic residue at L34 (P = 0.0558);
MVP		0.72
ClinPred		0.26	T
GERP RS		2.4
Varity_R		0.077
gMVP		0.57

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: rs369845234; hg19: chr10-79397316;