chr10-76944983-G-GA

Variant names:

• chr10-76944983-G-GA
• rs112408409
• NM_001161352.2:c.2710-19dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001161352.2(KCNMA1):​c.2710-19dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 1,529,182 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (22 hom.)
• Consequence: KCNMA1 NM_001161352.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.262
• 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 -16 ACMG points.

• BP6: Variant 10-76944983-G-GA is Benign according to our data. Variant chr10-76944983-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00993 (1479/148974) while in subpopulation AFR AF = 0.0333 (1350/40570). AF 95% confidence interval is 0.0318. There are 18 homozygotes in GnomAd4. There are 714 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.2710-19dupT		intron	N/A	NP_001154824.1
	KCNMA1	NM_001437422.1		c.2668-19dupT		intron	N/A	NP_001424351.1
	KCNMA1	NM_001161353.2		c.2659-19dupT		intron	N/A	NP_001154825.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.2710-19_2710-18insT		intron	N/A	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.2659-19_2659-18insT		intron	N/A	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.2545-19_2545-18insT		intron	N/A	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1479 AN: 148864 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000406

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.000924

Gnomad OTH AF: 0.00688

GnomAD2 exomes AF: 0.00398 AC: 879 AN: 220710 AF XY: 0.00332

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000219

Gnomad EAS exome AF: 0.000499

Gnomad FIN exome AF: 0.00173

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.00190

GnomAD4 exome AF: 0.00420 AC: 5796 AN: 1380208 Hom.: 22 Cov.: 30 AF XY: 0.00378 AC XY: 2599 AN XY: 688020

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

African (AFR) AF: 0.0384 AC: 1204 AN: 31316

American (AMR) AF: 0.00218 AC: 91 AN: 41776

Ashkenazi Jewish (ASJ) AF: 0.00102 AC: 25 AN: 24530

East Asian (EAS) AF: 0.000907 AC: 34 AN: 37492

South Asian (SAS) AF: 0.00114 AC: 94 AN: 82600

European-Finnish (FIN) AF: 0.00151 AC: 76 AN: 50398

Middle Eastern (MID) AF: 0.00385 AC: 21 AN: 5460

European-Non Finnish (NFE) AF: 0.00377 AC: 3961 AN: 1050030

Other (OTH) AF: 0.00512 AC: 290 AN: 56606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00993 AC: 1479 AN: 148974 Hom.: 18 Cov.: 32 AF XY: 0.00984 AC XY: 714 AN XY: 72562

African (AFR) AF: 0.0333 AC: 1350 AN: 40570

American (AMR) AF: 0.00300 AC: 45 AN: 14984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4690

European-Finnish (FIN) AF: 0.000406 AC: 4 AN: 9844

Middle Eastern (MID) AF: 0.0104 AC: 3 AN: 288

European-Non Finnish (NFE) AF: 0.000924 AC: 62 AN: 67100

Other (OTH) AF: 0.00681 AC: 14 AN: 2056

Alfa AF: 0.00224 Hom.: 0

Bravo AF: 0.0113

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26
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: rs112408409; hg19: chr10-78704741; COSMIC: COSV54253529; COSMIC: COSV54253529;