7-81950272-A-T

Variant names:

• chr7-81950272-A-T
• rs78368203
• NM_000722.4:c.*120T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000722.4(CACNA2D1):​c.*120T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,589,544 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (130 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (134 hom.)
• Consequence: CACNA2D1 NM_000722.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.604
• Publications: 2 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
• Brugada syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp
• genetic developmental and epileptic encephalopathy

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

  Inheritance: AR Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-81950272-A-T is Benign according to our data. Variant chr7-81950272-A-T is described in ClinVar as Benign. ClinVar VariationId is 1226581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

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.*120T>A		3_prime_UTR	Exon 39 of 39	NP_000713.2	P54289-2
	CACNA2D1	NM_001366867.1		c.*120T>A		3_prime_UTR	Exon 39 of 39	NP_001353796.1	P54289-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA2D1	ENST00000356860.8	TSL:1 MANE Select	c.*120T>A		3_prime_UTR	Exon 39 of 39	ENSP00000349320.3	P54289-2
	CACNA2D1	ENST00000443883.2	TSL:5	c.*120T>A		3_prime_UTR	Exon 39 of 39	ENSP00000409374.2	H0Y715
	CACNA2D1	ENST00000957014.1		c.*120T>A		3_prime_UTR	Exon 39 of 39	ENSP00000627073.1

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3645 AN: 152026 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.00352 AC: 5058 AN: 1437400 Hom.: 134 Cov.: 27 AF XY: 0.00322 AC XY: 2305 AN XY: 715606

African (AFR) AF: 0.0810 AC: 2679 AN: 33060

American (AMR) AF: 0.00930 AC: 406 AN: 43676

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 536 AN: 25630

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39486

South Asian (SAS) AF: 0.00104 AC: 88 AN: 84388

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50600

Middle Eastern (MID) AF: 0.0104 AC: 54 AN: 5214

European-Non Finnish (NFE) AF: 0.000670 AC: 734 AN: 1095810

Other (OTH) AF: 0.00939 AC: 559 AN: 59536

GnomAD4 genome AF: 0.0242 AC: 3677 AN: 152144 Hom.: 130 Cov.: 32 AF XY: 0.0242 AC XY: 1799 AN XY: 74394

African (AFR) AF: 0.0780 AC: 3240 AN: 41512

American (AMR) AF: 0.0150 AC: 229 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 98 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000927 AC: 63 AN: 67992

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.0190 Hom.: 14

Bravo AF: 0.0272

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.66
DANN	Benign	0.61
PhyloP100		-0.60
Mutation Taster		=100/0	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: rs78368203; hg19: chr7-81579588;