22-36674126-A-T

Variant names:

• chr22-36674126-A-T
• rs916269
• NM_006078.5:c.211+28240T>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+28240T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 152,022 control chromosomes in the GnomAD database, including 15,482 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 0.41 (15482 hom., cov: 32)
• Consequence: CACNG2 NM_006078.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 2 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNG2	NM_006078.5	c.211+28240T>A		intron_variant	Intron 1 of 3	ENST00000300105.7	NP_006069.1
CACNG2	NM_001379051.1	c.142+28240T>A		intron_variant	Intron 2 of 4		NP_001365980.1
CACNG2	NR_166440.1	n.1387+28240T>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+28240T>A		intron_variant	Intron 1 of 3	1	NM_006078.5	ENSP00000300105.6

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62754 AN: 151906 Hom.: 15442 Cov.: 32

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.396

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

GnomAD4 genome AF: 0.413 AC: 62847 AN: 152022 Hom.: 15482 Cov.: 32 AF XY: 0.412 AC XY: 30599 AN XY: 74298

African (AFR) AF: 0.692 AC: 28688 AN: 41476

American (AMR) AF: 0.290 AC: 4441 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1447 AN: 3472

East Asian (EAS) AF: 0.173 AC: 888 AN: 5142

South Asian (SAS) AF: 0.321 AC: 1545 AN: 4820

European-Finnish (FIN) AF: 0.350 AC: 3699 AN: 10560

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20900 AN: 67946

Other (OTH) AF: 0.393 AC: 830 AN: 2110

Alfa AF: 0.186 Hom.: 336

Bravo AF: 0.421

Asia WGS AF: 0.318 AC: 1112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0060
DANN	Benign	0.66
PhyloP100		-1.9
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: rs916269; hg19: chr22-37070172;