10-77637554-T-C

Variant names:

• chr10-77637554-T-C
• rs200474297
• NM_001161352.2:c.89A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001161352.2(KCNMA1):​c.89A>G​(p.His30Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000682 in 1,543,398 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H30Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 3.88
• Publications: 2 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03433919).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000395 (60/151816) while in subpopulation NFE AF = 0.000648 (44/67922). AF 95% confidence interval is 0.000495. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.89A>G	p.His30Arg	missense	Exon 1 of 28	NP_001154824.1
	KCNMA1	NM_001437422.1		c.89A>G	p.His30Arg	missense	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.89A>G	p.His30Arg	missense	Exon 1 of 28	NP_001154825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.89A>G	p.His30Arg	missense	Exon 1 of 28	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.89A>G	p.His30Arg	missense	Exon 1 of 28	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.89A>G	p.His30Arg	missense	Exon 1 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.000395 AC: 60 AN: 151816 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

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: 0.000850

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000648

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000241 AC: 36 AN: 149244 AF XY: 0.000251

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 FIN exome AF: 0.00105

Gnomad NFE exome AF: 0.000416

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000714 AC: 993 AN: 1391582 Hom.: 0 Cov.: 30 AF XY: 0.000710 AC XY: 488 AN XY: 687174

African (AFR) AF: 0.000127 AC: 4 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 36060

Ashkenazi Jewish (ASJ) AF: 0.0000794 AC: 2 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 35882

South Asian (SAS) AF: 0.00 AC: 0 AN: 79496

European-Finnish (FIN) AF: 0.000952 AC: 42 AN: 44132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.000863 AC: 928 AN: 1075668

Other (OTH) AF: 0.000293 AC: 17 AN: 57924

GnomAD4 genome AF: 0.000395 AC: 60 AN: 151816 Hom.: 0 Cov.: 33 AF XY: 0.000418 AC XY: 31 AN XY: 74144

African (AFR) AF: 0.000169 AC: 7 AN: 41336

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000850 AC: 9 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000648 AC: 44 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000283

ExAC AF: 0.000114 AC: 12

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	1	Generalized epilepsy-paroxysmal dyskinesia syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.092	T
Polyphen		0.0010	B
Vest4		0.21
MutPred		0.28		Gain of MoRF binding (P = 0.0122)
MVP		0.60
ClinPred		0.23	T
GERP RS		3.5
PromoterAI		0.14	Neutral
Varity_R		0.13
gMVP		0.41
Mutation Taster		=79/21	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: rs200474297; hg19: chr10-79397312;