22-36701519-C-T

Variant names:

• chr22-36701519-C-T
• rs2284018
• NM_006078.5:c.211+847G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006078.5(CACNG2):​c.211+847G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 148,114 control chromosomes in the GnomAD database, including 4,220 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 0.23 (4220 hom., cov: 26)
• Consequence: CACNG2 NM_006078.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 11 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNG2	NM_006078.5	c.211+847G>A		intron_variant	Intron 1 of 3	ENST00000300105.7	NP_006069.1
CACNG2	NM_001379051.1	c.142+847G>A		intron_variant	Intron 2 of 4		NP_001365980.1
CACNG2	NR_166440.1	n.1387+847G>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNG2	ENST00000300105.7	c.211+847G>A		intron_variant	Intron 1 of 3	1	NM_006078.5	ENSP00000300105.6

Frequencies

GnomAD3 genomes AF: 0.231 AC: 34195 AN: 148000 Hom.: 4226 Cov.: 26

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.235

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

GnomAD4 genome AF: 0.231 AC: 34192 AN: 148114 Hom.: 4220 Cov.: 26 AF XY: 0.231 AC XY: 16613 AN XY: 71876

African (AFR) AF: 0.165 AC: 6656 AN: 40288

American (AMR) AF: 0.227 AC: 3348 AN: 14754

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 692 AN: 3452

East Asian (EAS) AF: 0.290 AC: 1431 AN: 4934

South Asian (SAS) AF: 0.287 AC: 1312 AN: 4566

European-Finnish (FIN) AF: 0.306 AC: 2954 AN: 9642

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.253 AC: 17003 AN: 67224

Other (OTH) AF: 0.233 AC: 480 AN: 2062

Alfa AF: 0.244 Hom.: 8118

Asia WGS AF: 0.259 AC: 896 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.86
PhyloP100		1.3
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: rs2284018; hg19: chr22-37097564; COSMIC: COSV55638126; COSMIC: COSV55638126;