rs2229009

Variant names:

• chr10-76949286-G-A
• rs2229009
• NM_001161352.2:c.2565C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-76949286-G-A
• chr10-76949286-G-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_001161352.2(KCNMA1):​c.2565C>T​(p.Ile855Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,614,094 control chromosomes in the GnomAD database, including 141 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (126 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.855
• 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-AS1 (HGNC:51213): (KCNMA1 antisense RNA 1)

LOC124902466 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP6: Variant 10-76949286-G-A is Benign according to our data. Variant chr10-76949286-G-A is described in ClinVar as Benign. ClinVar VariationId is 195587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.855 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00408 (621/152224) while in subpopulation SAS AF = 0.0425 (205/4820). AF 95% confidence interval is 0.0378. There are 15 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.2565C>T	p.Ile855Ile	synonymous	Exon 22 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.2523C>T	p.Ile841Ile	synonymous	Exon 22 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.2514C>T	p.Ile838Ile	synonymous	Exon 22 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.2565C>T	p.Ile855Ile	synonymous	Exon 22 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.2514C>T	p.Ile838Ile	synonymous	Exon 22 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.2400C>T	p.Ile800Ile	synonymous	Exon 22 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 607 AN: 152106 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00915

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00610 AC: 1532 AN: 251224 AF XY: 0.00799

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00300 AC: 4390 AN: 1461870 Hom.: 126 Cov.: 31 AF XY: 0.00417 AC XY: 3036 AN XY: 727236

African (AFR) AF: 0.00956 AC: 320 AN: 33478

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0432 AC: 3724 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1111998

Other (OTH) AF: 0.00301 AC: 182 AN: 60394

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152224 Hom.: 15 Cov.: 32 AF XY: 0.00468 AC XY: 348 AN XY: 74418

African (AFR) AF: 0.00944 AC: 392 AN: 41534

American (AMR) AF: 0.000458 AC: 7 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.0425 AC: 205 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00143 Hom.: 2

Bravo AF: 0.00318

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	9.0
DANN	Benign	0.88
PhyloP100		0.85
Mutation Taster		=97/3	polymorphism (auto)

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: rs2229009; hg19: chr10-78709044; COSMIC: COSV54274621;