rs780558929

Variant names:

• chr10-77637627-C-CGCT
• rs780558929
• NM_001161352.2:c.15_16insAGC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS1

The NM_001161352.2(KCNMA1):​c.15_16insAGC​(p.Gly5_Gly6insSer) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,523,288 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G5G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 3.25
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001161352.2
• BP6: Variant 10-77637627-C-CGCT is Benign according to our data. Variant chr10-77637627-C-CGCT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 300975.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000926 (14/151228) while in subpopulation EAS AF = 0.00236 (12/5084). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.15_16insAGC	p.Gly5_Gly6insSer	conservative_inframe_insertion	Exon 1 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.15_16insAGC	p.Gly5_Gly6insSer	conservative_inframe_insertion	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.15_16insAGC	p.Gly5_Gly6insSer	conservative_inframe_insertion	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.15_16insAGC	p.Gly5_Gly6insSer	conservative_inframe_insertion	Exon 1 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.15_16insAGC	p.Gly5_Gly6insSer	conservative_inframe_insertion	Exon 1 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.15_16insAGC	p.Gly5_Gly6insSer	conservative_inframe_insertion	Exon 1 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes AF: 0.0000926 AC: 14 AN: 151228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00236

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000440 AC: 54 AN: 122676 AF XY: 0.000462

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000856

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00495

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000262

GnomAD4 exome AF: 0.0000692 AC: 95 AN: 1372060 Hom.: 0 Cov.: 33 AF XY: 0.0000695 AC XY: 47 AN XY: 676418

African (AFR) AF: 0.00 AC: 0 AN: 30984

American (AMR) AF: 0.0000577 AC: 2 AN: 34642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24286

East Asian (EAS) AF: 0.00147 AC: 52 AN: 35368

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4816

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072584

Other (OTH) AF: 0.000699 AC: 40 AN: 57246

GnomAD4 genome AF: 0.0000926 AC: 14 AN: 151228 Hom.: 0 Cov.: 32 AF XY: 0.0000542 AC XY: 4 AN XY: 73814

African (AFR) AF: 0.00 AC: 0 AN: 41140

American (AMR) AF: 0.000131 AC: 2 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00236 AC: 12 AN: 5084

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67706

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000843 Hom.: 0

Asia WGS AF: 0.00233 AC: 8 AN: 3454

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	Generalized epilepsy-paroxysmal dyskinesia syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=79/21	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs780558929; hg19: chr10-79397385;