rs140526

Variant names:

• chr22-36637217-T-G
• rs140526
• NM_006078.5:c.212-49669A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_006078.5(CACNG2):​c.212-49669A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 152,004 control chromosomes in the GnomAD database, including 29,883 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 0.60 (29883 hom., cov: 32)
• Consequence: CACNG2 NM_006078.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.550
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNG2	NM_006078.5	c.212-49669A>C		intron_variant	Intron 1 of 3	ENST00000300105.7	NP_006069.1
CACNG2	NM_001379051.1	c.143-49669A>C		intron_variant	Intron 2 of 4		NP_001365980.1
CACNG2	NR_166440.1	n.1388-49669A>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNG2	ENST00000300105.7	c.212-49669A>C		intron_variant	Intron 1 of 3	1	NM_006078.5	ENSP00000300105.6

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90969 AN: 151886 Hom.: 29862 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.712

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.599 AC: 91028 AN: 152004 Hom.: 29883 Cov.: 32 AF XY: 0.607 AC XY: 45106 AN XY: 74304

African (AFR) AF: 0.308 AC: 12729 AN: 41378

American (AMR) AF: 0.712 AC: 10886 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1930 AN: 3470

East Asian (EAS) AF: 0.845 AC: 4378 AN: 5180

South Asian (SAS) AF: 0.717 AC: 3461 AN: 4824

European-Finnish (FIN) AF: 0.752 AC: 7958 AN: 10580

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.701 AC: 47612 AN: 67968

Other (OTH) AF: 0.606 AC: 1282 AN: 2114

Alfa AF: 0.665 Hom.: 68511

Bravo AF: 0.582

Asia WGS AF: 0.721 AC: 2504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		0.55
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: rs140526; hg19: chr22-37033264;