NM_001161352.2:c.*1288A>T

Variant names:

• chr10-76885978-T-A
• rs78082918
• NM_001161352.2:c.*1288A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001161352.2(KCNMA1):​c.*1288A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 985,414 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0084 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (13 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.169
• Publications: 1 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, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-76885978-T-A is Benign according to our data. Variant chr10-76885978-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 300934.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00837 (1274/152288) while in subpopulation AFR AF = 0.0275 (1141/41562). AF 95% confidence interval is 0.0261. There are 19 homozygotes in GnomAd4. There are 615 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.*1288A>T		3_prime_UTR	Exon 28 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.*1288A>T		3_prime_UTR	Exon 28 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.*1288A>T		3_prime_UTR	Exon 28 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.*1288A>T		3_prime_UTR	Exon 28 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000639406.1	TSL:1	c.*1288A>T		3_prime_UTR	Exon 29 of 29	ENSP00000491732.1	B7ZMF5
	KCNMA1	ENST00000286627.10	TSL:1	c.*1288A>T		3_prime_UTR	Exon 27 of 27	ENSP00000286627.5	Q12791-5

Frequencies

GnomAD3 genomes AF: 0.00827 AC: 1259 AN: 152170 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.000709 AC: 591 AN: 833126 Hom.: 13 Cov.: 32 AF XY: 0.000697 AC XY: 268 AN XY: 384726

African (AFR) AF: 0.0318 AC: 502 AN: 15786

American (AMR) AF: 0.00102 AC: 1 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.000194 AC: 1 AN: 5152

East Asian (EAS) AF: 0.00 AC: 0 AN: 3632

South Asian (SAS) AF: 0.000122 AC: 2 AN: 16460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 276

Middle Eastern (MID) AF: 0.00247 AC: 4 AN: 1620

European-Non Finnish (NFE) AF: 0.0000341 AC: 26 AN: 761908

Other (OTH) AF: 0.00201 AC: 55 AN: 27308

GnomAD4 genome AF: 0.00837 AC: 1274 AN: 152288 Hom.: 19 Cov.: 32 AF XY: 0.00826 AC XY: 615 AN XY: 74458

African (AFR) AF: 0.0275 AC: 1141 AN: 41562

American (AMR) AF: 0.00693 AC: 106 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68028

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00945

Asia WGS AF: 0.00289 AC: 10 AN: 3478

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
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.64
PhyloP100		-0.17
Mutation Taster		=100/0	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: rs78082918; hg19: chr10-78645736;