NM_000069.3:c.1995C>T

Variant names:

• chr1-201074574-G-A
• rs16847664
• NM_000069.3:c.1995C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000069.3(CACNA1S):​c.1995C>T​(p.Ala665Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,613,926 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A665A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (97 hom., cov: 34)
  • Exomes 𝑓: 0.0030 (94 hom.)
• Consequence: CACNA1S NM_000069.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -5.01
• Publications: 1 publications found

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

CACNA1S Gene-Disease associations (from GenCC):

• hypokalemic periodic paralysis, type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• malignant hyperthermia, susceptibility to, 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital myopathy 18

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: SD, AD, AR Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-201074574-G-A is Benign according to our data. Variant chr1-201074574-G-A is described in ClinVar as Benign. ClinVar VariationId is 254809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000069.3. 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
	CACNA1S	NM_000069.3	MANE Select	c.1995C>T	p.Ala665Ala	synonymous	Exon 14 of 44	NP_000060.2	Q13698

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.1995C>T	p.Ala665Ala	synonymous	Exon 14 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.1995C>T	p.Ala665Ala	synonymous	Exon 14 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.1995C>T	p.Ala665Ala	synonymous	Exon 14 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2830 AN: 152174 Hom.: 97 Cov.: 34

Gnomad AFR AF: 0.0609

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00657 AC: 1649 AN: 251148 AF XY: 0.00529

Gnomad AFR exome AF: 0.0606

Gnomad AMR exome AF: 0.00362

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00295 AC: 4315 AN: 1461634 Hom.: 94 Cov.: 31 AF XY: 0.00271 AC XY: 1973 AN XY: 727100

African (AFR) AF: 0.0658 AC: 2203 AN: 33472

American (AMR) AF: 0.00436 AC: 195 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 1083 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86200

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53412

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.000367 AC: 408 AN: 1111876

Other (OTH) AF: 0.00669 AC: 404 AN: 60382

GnomAD4 genome AF: 0.0186 AC: 2831 AN: 152292 Hom.: 97 Cov.: 34 AF XY: 0.0178 AC XY: 1327 AN XY: 74466

African (AFR) AF: 0.0608 AC: 2525 AN: 41552

American (AMR) AF: 0.00621 AC: 95 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68018

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0132 Hom.: 34

Bravo AF: 0.0214

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Malignant hyperthermia, susceptibility to, 5 (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.8
DANN	Benign	0.71
PhyloP100		-5.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16847664; hg19: chr1-201043702;