rs6000351

Variant names:

• chr22-36614820-G-A
• rs6000351
• NM_006078.5:c.212-27272C>T

Variant summary

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

The NM_006078.5(CACNG2):​c.212-27272C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0992 in 152,246 control chromosomes in the GnomAD database, including 804 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 0.099 (804 hom., cov: 32)
• Consequence: CACNG2 NM_006078.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNG2	NM_006078.5	c.212-27272C>T		intron_variant	Intron 1 of 3	ENST00000300105.7	NP_006069.1
CACNG2	NM_001379051.1	c.143-27272C>T		intron_variant	Intron 2 of 4		NP_001365980.1
CACNG2	NR_166440.1	n.1388-27272C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNG2	ENST00000300105.7	c.212-27272C>T		intron_variant	Intron 1 of 3	1	NM_006078.5	ENSP00000300105.6

Frequencies

GnomAD3 genomes AF: 0.0991 AC: 15082 AN: 152128 Hom.: 802 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.0837

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.120

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

GnomAD4 genome AF: 0.0992 AC: 15099 AN: 152246 Hom.: 804 Cov.: 32 AF XY: 0.0957 AC XY: 7126 AN XY: 74436

African (AFR) AF: 0.112 AC: 4664 AN: 41538

American (AMR) AF: 0.101 AC: 1551 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 463 AN: 3468

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5194

South Asian (SAS) AF: 0.0830 AC: 400 AN: 4820

European-Finnish (FIN) AF: 0.0353 AC: 375 AN: 10614

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7142 AN: 68002

Other (OTH) AF: 0.119 AC: 251 AN: 2114

Alfa AF: 0.105 Hom.: 1580

Bravo AF: 0.103

Asia WGS AF: 0.0500 AC: 172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.74
DANN	Benign	0.85
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: rs6000351; hg19: chr22-37010867;