22-36612881-A-G

Variant names:

• chr22-36612881-A-G
• rs738977
• NM_006078.5:c.212-25333T>C

Variant summary

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

The NM_006078.5(CACNG2):​c.212-25333T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 152,090 control chromosomes in the GnomAD database, including 40,241 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 0.72 (40241 hom., cov: 32)
• Consequence: CACNG2 NM_006078.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373
• Publications: 4 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006078.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNG2	NM_006078.5	MANE Select	c.212-25333T>C		intron	N/A	NP_006069.1
	CACNG2	NM_001379051.1		c.143-25333T>C		intron	N/A	NP_001365980.1
	CACNG2	NR_166440.1		n.1388-25333T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNG2	ENST00000300105.7	TSL:1 MANE Select	c.212-25333T>C		intron	N/A	ENSP00000300105.6

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109353 AN: 151970 Hom.: 40214 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.969

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.710

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

GnomAD4 genome AF: 0.719 AC: 109427 AN: 152090 Hom.: 40241 Cov.: 32 AF XY: 0.725 AC XY: 53873 AN XY: 74330

African (AFR) AF: 0.563 AC: 23358 AN: 41452

American (AMR) AF: 0.793 AC: 12129 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2320 AN: 3470

East Asian (EAS) AF: 0.969 AC: 5026 AN: 5188

South Asian (SAS) AF: 0.741 AC: 3568 AN: 4818

European-Finnish (FIN) AF: 0.825 AC: 8726 AN: 10574

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51869 AN: 67986

Other (OTH) AF: 0.714 AC: 1506 AN: 2110

Alfa AF: 0.746 Hom.: 7225

Bravo AF: 0.713

Asia WGS AF: 0.811 AC: 2818 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.26
PhyloP100		-0.37
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: rs738977; hg19: chr22-37008928;