19-53982253-A-T

Position:

• chr19-53982253-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031895.6(CACNG8):​c.682A>T​(p.Ile228Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,344 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNG8 NM_031895.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59

Genes affected

CACNG8 (HGNC:13628): (calcium voltage-gated channel auxiliary subunit gamma 8) 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. 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 II TARP and a calcium channel gamma subunit. The mRNA for this gene is believed to initiate translation from a non-AUG (CUG) start codon. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNG8	NM_031895.6	c.682A>T	p.Ile228Phe	missense_variant	4/4	ENST00000270458.4	NP_114101.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNG8	ENST00000270458.4	c.682A>T	p.Ile228Phe	missense_variant	4/4	1	NM_031895.6	ENSP00000270458.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460344 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 726508

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2024

The c.682A>T (p.I228F) alteration is located in exon 4 (coding exon 4) of the CACNG8 gene. This alteration results from a A to T substitution at nucleotide position 682, causing the isoleucine (I) at amino acid position 228 to be replaced by a phenylalanine (F). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	.;D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.0	D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.026	D;.
Polyphen		0.99	.;D
Vest4		0.85
MutPred		0.65		Gain of catalytic residue at I228 (P = 0.1503);Gain of catalytic residue at I228 (P = 0.1503);
MVP		0.35
ClinPred		0.96	D
GERP RS		1.8
Varity_R		0.13
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54485507;