Genetic Variant CACNG2:c.295+6537A>G (chr22-36580928-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006078.5(CACNG2):c.295+6537A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 151,854 control chromosomes in the GnomAD database, including 7,525 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7525 hom., cov: 32)

Consequence

CACNG2
NM_006078.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.852

Publications

6 publications found

Variant links:

Genes affected

CACNG2 (HGNC:1406): (calcium voltage-gated channel auxiliary subunit gamma 2) The protein encoded by this gene is a type I transmembrane AMPA receptor regulatory protein (TARP). TARPs regulate both trafficking and channel gating of the AMPA receptors. The AMPA subtype of ionotropic glutamate receptors are ligand gated ion channels that are typically activated by glutamate released from presynaptic neuron terminals and mediate fast neurotransmission in excitatory synapses. TARPs thus play an important role in synaptic plasticity, learning and memory. Mutations in this gene cause an autosomal dominant form of cognitive disability. [provided by RefSeq, Jul 2017]

CACNG2 Gene-Disease associations (from GenCC):

autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
intellectual disability, autosomal dominant 10
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CACNG2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CACNG2	NM_006078.5 link	c.295+6537A>G	intron_variant	Intron 2 of 3	ENST00000300105.7	NP_006069.1	Q9Y698
CACNG2	NM_001379051.1 link	c.226+6537A>G	intron_variant	Intron 3 of 4		NP_001365980.1
CACNG2	NR_166440.1 link	n.1471+6537A>G	intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNG2	ENST00000300105.7 link	c.295+6537A>G		intron_variant	Intron 2 of 3	1	NM_006078.5	ENSP00000300105.6		Q9Y698

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47318

AN:

151734

Hom.:

7512

Cov.:

show subpopulations

Gnomad AFR

AF:

0.344

Gnomad AMI

AF:

0.252

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.290

Gnomad EAS

AF:

0.198

Gnomad SAS

AF:

0.221

Gnomad FIN

AF:

0.290

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.316

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.312

AC:

47370

AN:

151854

Hom.:

7525

Cov.:

AF XY:

0.306

AC XY:

22709

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.344

AC:

14246

AN:

41376

American (AMR)

AF:

0.259

AC:

3944

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.290

AC:

1004

AN:

3466

East Asian (EAS)

AF:

0.198

AC:

1024

AN:

5172

South Asian (SAS)

AF:

0.223

AC:

1076

AN:

4826

European-Finnish (FIN)

AF:

0.290

AC:

3064

AN:

10550

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.324

AC:

22026

AN:

67898

Other (OTH)

AF:

0.320

AC:

676

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1701

3402

5104

6805

8506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<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:

0.316

Hom.:

32713

Bravo

AF:

0.311

Asia WGS

AF:

0.221

AC:

766

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.72

(source)

DANN

Benign

0.42

PhyloP100

-0.85

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over