rs77602559

Variant names:

• chr10-77637609-T-C
• rs77602559
• NM_001161352.2:c.34A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001161352.2(KCNMA1):​c.34A>G​(p.Ser12Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,520,716 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 0.101
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Illumina
• Liang-Wang syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• cerebellar atrophy, developmental delay, and seizures

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055193007).
• BP6: Variant 10-77637609-T-C is Benign according to our data. Variant chr10-77637609-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0057 (851/149174) while in subpopulation AFR AF = 0.0147 (597/40538). AF 95% confidence interval is 0.0137. There are 5 homozygotes in GnomAd4. There are 393 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

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.34A>G	p.Ser12Gly	missense	Exon 1 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.34A>G	p.Ser12Gly	missense	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.34A>G	p.Ser12Gly	missense	Exon 1 of 28	NP_001154825.1	Q12791-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.34A>G	p.Ser12Gly	missense	Exon 1 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.34A>G	p.Ser12Gly	missense	Exon 1 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.34A>G	p.Ser12Gly	missense	Exon 1 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 850 AN: 149072 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00532

Gnomad ASJ AF: 0.00146

Gnomad EAS AF: 0.00242

Gnomad SAS AF: 0.000866

Gnomad FIN AF: 0.00116

Gnomad MID AF: 0.00671

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00491

GnomAD2 exomes AF: 0.00204 AC: 255 AN: 125036 AF XY: 0.00200

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.00140

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00338

GnomAD4 exome AF: 0.00182 AC: 2496 AN: 1371542 Hom.: 4 Cov.: 33 AF XY: 0.00178 AC XY: 1201 AN XY: 676296

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0130 AC: 399 AN: 30732

American (AMR) AF: 0.00379 AC: 131 AN: 34548

Ashkenazi Jewish (ASJ) AF: 0.00163 AC: 40 AN: 24556

East Asian (EAS) AF: 0.00187 AC: 66 AN: 35206

South Asian (SAS) AF: 0.000860 AC: 67 AN: 77920

European-Finnish (FIN) AF: 0.00167 AC: 59 AN: 35334

Middle Eastern (MID) AF: 0.00441 AC: 22 AN: 4992

European-Non Finnish (NFE) AF: 0.00145 AC: 1550 AN: 1071072

Other (OTH) AF: 0.00283 AC: 162 AN: 57182

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00570 AC: 851 AN: 149174 Hom.: 5 Cov.: 32 AF XY: 0.00539 AC XY: 393 AN XY: 72928

African (AFR) AF: 0.0147 AC: 597 AN: 40538

American (AMR) AF: 0.00531 AC: 80 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 5 AN: 3418

East Asian (EAS) AF: 0.00243 AC: 12 AN: 4936

South Asian (SAS) AF: 0.000867 AC: 4 AN: 4612

European-Finnish (FIN) AF: 0.00116 AC: 12 AN: 10372

Middle Eastern (MID) AF: 0.00725 AC: 2 AN: 276

European-Non Finnish (NFE) AF: 0.00193 AC: 129 AN: 67010

Other (OTH) AF: 0.00485 AC: 10 AN: 2060

Alfa AF: 0.00589 Hom.: 0

Bravo AF: 0.00637

ExAC AF: 0.000243 AC: 12

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Generalized epilepsy-paroxysmal dyskinesia syndrome (2)
-	1	-	Intellectual disability (1)
-	-	1	KCNMA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Benign	0.76
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.050	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.65
ClinPred		0.079	T
GERP RS		-1.6
PromoterAI		-0.0050	Neutral
Varity_R		0.066
gMVP		0.32
Mutation Taster		=98/2	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: rs77602559; hg19: chr10-79397367;