19-53914502-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_031896.5(CACNG7):c.199C>T(p.Arg67Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CACNG7
NM_031896.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.449

Variant links:

Genes affected

CACNG7 (HGNC:13626): (calcium voltage-gated channel auxiliary subunit gamma 7) The protein encoded by this gene is a type II transmembrane AMPA receptor regulatory protein (TARP). TARPs regulate both trafficking and channel gating of the AMPA receptors. This gene is part of a functionally diverse eight-member protein subfamily of the PMP-22/EMP/MP20 family and is located in a cluster with two family members, a type I TARP and a calcium channel gamma subunit. [provided by RefSeq, Dec 2010]

CACNG7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3471134).

BS2

High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNG7	NM_031896.5 link	c.199C>T	p.Arg67Trp	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000391767.6	NP_114102.2	P62955
CACNG7	NM_001384801.1 link	c.199C>T	p.Arg67Trp	missense_variant, splice_region_variant	Exon 3 of 5		NP_001371730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNG7	ENST00000391767.6 link	c.199C>T	p.Arg67Trp	missense_variant, splice_region_variant	Exon 3 of 6	5	NM_031896.5	ENSP00000375647.1	P62955
CACNG7	ENST00000222212.6 link	c.199C>T	p.Arg67Trp	missense_variant, splice_region_variant	Exon 2 of 5	1		ENSP00000222212.2	P62955
CACNG7	ENST00000391766.1 link	c.199C>T	p.Arg67Trp	missense_variant, splice_region_variant	Exon 2 of 4	1		ENSP00000375646.1	A0A0C4DFY2
CACNG7	ENST00000468076.5 link	n.184-863C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

250038

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135278

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199C>T (p.R67W) alteration is located in exon 2 (coding exon 2) of the CACNG7 gene. This alteration results from a C to T substitution at nucleotide position 199, causing the arginine (R) at amino acid position 67 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T;.

Eigen

Benign

0.032

Eigen_PC

Benign

-0.028

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.0

L;L;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.017

D;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

0.92

P;P;.

Vest4

0.61

MutPred

0.50

Loss of methylation at R67 (P = 0.0311);Loss of methylation at R67 (P = 0.0311);Loss of methylation at R67 (P = 0.0311);

MVP

0.81

MPC

1.6

ClinPred

0.57

GERP RS

3.1

Varity_R

0.14

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over