chr10-76891672-G-A

Variant names:

• chr10-76891672-G-A
• rs45527834
• NM_001161352.2:c.3195C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001161352.2(KCNMA1):​c.3195C>T​(p.Thr1065Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,614,022 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts 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: 0.0081 (67 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.12
• 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-AS1 (HGNC:51213): (KCNMA1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.095).
• BP6: Variant 10-76891672-G-A is Benign according to our data. Variant chr10-76891672-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00573 (872/152270) while in subpopulation NFE AF = 0.00948 (645/68004). AF 95% confidence interval is 0.00888. There are 5 homozygotes in GnomAd4. There are 398 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.3195C>T	p.Thr1065Thr	synonymous	Exon 26 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.3153C>T	p.Thr1051Thr	synonymous	Exon 26 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.3144C>T	p.Thr1048Thr	synonymous	Exon 26 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.3195C>T	p.Thr1065Thr	synonymous	Exon 26 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.3144C>T	p.Thr1048Thr	synonymous	Exon 26 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.3111C>T	p.Thr1037Thr	synonymous	Exon 27 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152152 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00948

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00570 AC: 1431 AN: 250884 AF XY: 0.00585

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00283

Gnomad NFE exome AF: 0.00835

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00809 AC: 11823 AN: 1461752 Hom.: 67 Cov.: 31 AF XY: 0.00789 AC XY: 5734 AN XY: 727190

African (AFR) AF: 0.00155 AC: 52 AN: 33480

American (AMR) AF: 0.00338 AC: 151 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 397 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00379 AC: 327 AN: 86258

European-Finnish (FIN) AF: 0.00308 AC: 164 AN: 53326

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.00925 AC: 10289 AN: 1111968

Other (OTH) AF: 0.00669 AC: 404 AN: 60392

GnomAD4 genome AF: 0.00573 AC: 872 AN: 152270 Hom.: 5 Cov.: 32 AF XY: 0.00535 AC XY: 398 AN XY: 74446

African (AFR) AF: 0.00137 AC: 57 AN: 41570

American (AMR) AF: 0.00261 AC: 40 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4824

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00948 AC: 645 AN: 68004

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00631 Hom.: 1

Bravo AF: 0.00529

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00759

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Generalized epilepsy-paroxysmal dyskinesia syndrome (5)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.43
DANN	Benign	0.86
PhyloP100		-2.1
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: rs45527834; hg19: chr10-78651430;