Genetic Variant CACNG2:c.212-12C>A (chr22-36587560-G-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006078.5(CACNG2):c.212-12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,595,580 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 20 hom. )

Consequence

CACNG2
NM_006078.5 intron

Scores

Splicing: ADA: 0.00005386

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.633

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 22-36587560-G-T is Benign according to our data. Variant chr22-36587560-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 376862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 409 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CACNG2	NM_006078.5 link	c.212-12C>A	intron_variant	Intron 1 of 3	ENST00000300105.7	NP_006069.1
CACNG2	NM_001379051.1 link	c.143-12C>A	intron_variant	Intron 2 of 4		NP_001365980.1
CACNG2	NR_166440.1 link	n.1388-12C>A	intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNG2	ENST00000300105.7 link	c.212-12C>A		intron_variant	Intron 1 of 3	1	NM_006078.5	ENSP00000300105.6

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

409

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00410

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00303

AC:

763

AN:

251432

AF XY:

0.00315

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00744

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00115

Gnomad NFE exome

AF:

0.00451

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00410

AC:

5919

AN:

1443244

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

2898

AN XY:

719270

show subpopulations

African (AFR)

AF:

0.000513

AC:

AN:

33110

American (AMR)

AF:

0.00154

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00718

AC:

187

AN:

26044

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39614

South Asian (SAS)

AF:

0.00278

AC:

239

AN:

85950

European-Finnish (FIN)

AF:

0.00107

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00466

AC:

5104

AN:

1094926

Other (OTH)

AF:

0.00390

AC:

233

AN:

59770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

261

522

783

1044

1305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

194

388

582

776

970

<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:

0.00268

AC:

409

AN:

152336

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41572

American (AMR)

AF:

0.00222

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00951

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00228

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00410

AC:

279

AN:

68032

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

115

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:

0.00252

Hom.:

Bravo

AF:

0.00282

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.63

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000054

dbscSNV1_RF

Benign

0.036

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over