22-36570195-G-T

Variant names:

• chr22-36570195-G-T
• rs2267339
• NM_006078.5:c.296-3702C>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.296-3702C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,104 control chromosomes in the GnomAD database, including 9,266 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 0.35 (9266 hom., cov: 32)
• Consequence: CACNG2 NM_006078.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.585
• Publications: 6 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=-0.75).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.361 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.296-3702C>A		intron	N/A	NP_006069.1
	CACNG2	NM_001379051.1		c.227-3702C>A		intron	N/A	NP_001365980.1
	CACNG2	NR_166440.1		n.1472-3702C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNG2	ENST00000300105.7	TSL:1 MANE Select	c.296-3702C>A		intron	N/A	ENSP00000300105.6

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52759 AN: 151986 Hom.: 9260 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.347 AC: 52784 AN: 152104 Hom.: 9266 Cov.: 32 AF XY: 0.348 AC XY: 25919 AN XY: 74374

African (AFR) AF: 0.351 AC: 14567 AN: 41508

American (AMR) AF: 0.369 AC: 5646 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3472

East Asian (EAS) AF: 0.288 AC: 1488 AN: 5158

South Asian (SAS) AF: 0.320 AC: 1541 AN: 4816

European-Finnish (FIN) AF: 0.370 AC: 3914 AN: 10592

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23442 AN: 67948

Other (OTH) AF: 0.335 AC: 706 AN: 2110

Alfa AF: 0.336 Hom.: 14325

Bravo AF: 0.349

Asia WGS AF: 0.300 AC: 1046 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.7
DANN	Benign	0.93
PhyloP100		0.58
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: rs2267339; hg19: chr22-36966242;