10-77637612-TGCCGCCGCCGCC-TGCCGCCGCC

Variant names:

• chr10-77637612-TGCC-T
• rs750804948
• NM_001161352.2:c.28_30delGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The ENST00000286628.14(KCNMA1):​c.28_30delGGC​(p.Gly10del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000441 in 1,519,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G10G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: KCNMA1 ENST00000286628.14 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• 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.

• BP3: Nonframeshift variant in repetitive region in ENST00000286628.14

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000286628.14. 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.28_30delGGC	p.Gly10del	conservative_inframe_deletion	Exon 1 of 28	NP_001154824.1
	KCNMA1	NM_001437422.1		c.28_30delGGC	p.Gly10del	conservative_inframe_deletion	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.28_30delGGC	p.Gly10del	conservative_inframe_deletion	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.28_30delGGC	p.Gly10del	conservative_inframe_deletion	Exon 1 of 28	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.28_30delGGC	p.Gly10del	conservative_inframe_deletion	Exon 1 of 28	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.28_30delGGC	p.Gly10del	conservative_inframe_deletion	Exon 1 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.0000536 AC: 8 AN: 149316 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000124

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000447

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000253 AC: 30 AN: 118702 AF XY: 0.000261

Gnomad AFR exome AF: 0.000585

Gnomad AMR exome AF: 0.0000449

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000630

Gnomad FIN exome AF: 0.000518

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.0000431 AC: 59 AN: 1370012 Hom.: 0 AF XY: 0.0000444 AC XY: 30 AN XY: 675472

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

African (AFR) AF: 0.0000325 AC: 1 AN: 30746

American (AMR) AF: 0.0000871 AC: 3 AN: 34424

Ashkenazi Jewish (ASJ) AF: 0.0000408 AC: 1 AN: 24502

East Asian (EAS) AF: 0.000313 AC: 11 AN: 35178

South Asian (SAS) AF: 0.0000772 AC: 6 AN: 77696

European-Finnish (FIN) AF: 0.0000570 AC: 2 AN: 35090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 0.0000308 AC: 33 AN: 1070296

Other (OTH) AF: 0.0000350 AC: 2 AN: 57126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000099587), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000536 AC: 8 AN: 149316 Hom.: 0 Cov.: 32 AF XY: 0.0000686 AC XY: 5 AN XY: 72930

African (AFR) AF: 0.000124 AC: 5 AN: 40454

American (AMR) AF: 0.00 AC: 0 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 4950

South Asian (SAS) AF: 0.00 AC: 0 AN: 4638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.0000447 AC: 3 AN: 67154

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
PhyloP100		1.5
Mutation Taster		=78/22	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: rs750804948; hg19: chr10-79397370; COSMIC: COSV54260472; COSMIC: COSV54260472;