Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001161352.2(KCNMA1):c.162_173delCTCTTCCTCCTC(p.Ser55_Ser58del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00176 in 1,610,310 control chromosomes in the GnomAD database, including 8 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 6 hom. )

Consequence

KCNMA1
NM_001161352.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:2

Conservation

PhyloP100: 3.85

Publications

0 publications found

Variant links:

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)

KCNMA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001161352.2

BP6

Variant 10-77637469-CGAGGAGGAAGAG-C is Benign according to our data. Variant chr10-77637469-CGAGGAGGAAGAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193230.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00187 (283/151572) while in subpopulation NFE AF = 0.00166 (113/67882). AF 95% confidence interval is 0.00142. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNMA1	NM_001161352.2	MANE Select	c.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	disruptive_inframe_deletion	Exon 1 of 28	NP_001154824.1
KCNMA1	NM_001437422.1		c.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	disruptive_inframe_deletion	Exon 1 of 28	NP_001424351.1
KCNMA1	NM_001161353.2		c.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	disruptive_inframe_deletion	Exon 1 of 28	NP_001154825.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	disruptive_inframe_deletion	Exon 1 of 28	ENSP00000286628.8
KCNMA1	ENST00000626620.3	TSL:1	c.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	disruptive_inframe_deletion	Exon 1 of 28	ENSP00000485867.1
KCNMA1	ENST00000639406.1	TSL:1	c.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	disruptive_inframe_deletion	Exon 1 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

283

AN:

151456

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000438

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000627

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00177

AC:

431

AN:

244132

AF XY:

0.00175

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.000499

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000667

GnomAD4 exome

AF:

0.00175

AC:

2548

AN:

1458738

Hom.:

AF XY:

0.00175

AC XY:

1272

AN XY:

725334

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33416

American (AMR)

AF:

0.000540

AC:

AN:

44450

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26010

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39638

South Asian (SAS)

AF:

0.000537

AC:

AN:

85602

European-Finnish (FIN)

AF:

0.0117

AC:

625

AN:

53198

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00160

AC:

1772

AN:

1110376

Other (OTH)

AF:

0.00106

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

125

250

376

501

626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00187

AC:

283

AN:

151572

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

168

AN XY:

74014

show subpopulations

African (AFR)

AF:

0.000436

AC:

AN:

41250

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.000628

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.0139

AC:

146

AN:

10504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00166

AC:

113

AN:

67882

Other (OTH)

AF:

0.00142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.000812

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Generalized epilepsy-paroxysmal dyskinesia syndrome (1)

KCNMA1-related disorder (1)

not specified (1)

Cerebellar atrophy, developmental delay, and seizures;C5574945:Generalized epilepsy-paroxysmal dyskinesia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.9

Mutation Taster

=197/3

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs754606765

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over