chr10-77637551-G-A

Variant names:

• chr10-77637551-G-A
• rs201551432
• NM_001161352.2:c.92C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_001161352.2(KCNMA1):​c.92C>T​(p.Ala31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,391,376 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A31T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.53
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3830775).
• BP6: Variant 10-77637551-G-A is Benign according to our data. Variant chr10-77637551-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1039907.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.92C>T	p.Ala31Val	missense	Exon 1 of 28	NP_001154824.1
	KCNMA1	NM_001437422.1		c.92C>T	p.Ala31Val	missense	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.92C>T	p.Ala31Val	missense	Exon 1 of 28	NP_001154825.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.92C>T	p.Ala31Val	missense	Exon 1 of 28	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.92C>T	p.Ala31Val	missense	Exon 1 of 28	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.92C>T	p.Ala31Val	missense	Exon 1 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000659 AC: 1 AN: 151682 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1391376 Hom.: 0 Cov.: 29 AF XY: 0.00000145 AC XY: 1 AN XY: 687310

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 36202

Ashkenazi Jewish (ASJ) AF: 0.000119 AC: 3 AN: 25186

East Asian (EAS) AF: 0.00 AC: 0 AN: 35956

South Asian (SAS) AF: 0.00 AC: 0 AN: 79578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074468

Other (OTH) AF: 0.00 AC: 0 AN: 57866

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Generalized epilepsy-paroxysmal dyskinesia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0051	T
Eigen	Benign	0.057
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.26	N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.11	T
Polyphen		0.064	B
Vest4		0.41
MutPred		0.24		Gain of sheet (P = 0.0125)
MVP		0.63
ClinPred		0.65	D
GERP RS		3.5
PromoterAI		-0.095	Neutral
Varity_R		0.11
gMVP		0.53
Mutation Taster		=82/18	polymorphism

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: rs201551432; hg19: chr10-79397309;