7-82084899-T-C

Variant names:

• chr7-82084899-T-C
• rs138577227
• NM_000722.4:c.528A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000722.4(CACNA2D1):​c.528A>G​(p.Ser176Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S176S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA2D1 NM_000722.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.002237
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0600
• Publications: 0 publications found

Genes affected

CACNA2D1 (HGNC:1399): (calcium voltage-gated channel auxiliary subunit alpha2delta 1) The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

CACNA2D1 Gene-Disease associations (from GenCC):

• short QT syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• developmental and epileptic encephalopathy 110

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Brugada syndrome

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 7-82084899-T-C is Benign according to our data. Variant chr7-82084899-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2565382.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.06 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000722.4. 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
	CACNA2D1	NM_000722.4	MANE Select	c.528A>G	p.Ser176Ser	splice_region synonymous	Exon 7 of 39	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.528A>G	p.Ser176Ser	splice_region synonymous	Exon 7 of 39	NP_001353796.1	P54289-1
	CACNA2D1	NM_001302890.2		c.528A>G	p.Ser176Ser	splice_region synonymous	Exon 7 of 11	NP_001289819.1	E7ERK3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.528A>G	p.Ser176Ser	splice_region synonymous	Exon 7 of 39	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000423588.1	TSL:1	c.528A>G	p.Ser176Ser	splice_region synonymous	Exon 7 of 11	ENSP00000405395.1	E7ERK3
	CACNA2D1	ENST00000443883.2	TSL:5	c.528A>G	p.Ser176Ser	splice_region synonymous	Exon 7 of 39	ENSP00000409374.2	H0Y715

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		-0.060

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.13
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: rs138577227; hg19: chr7-81714215;