chr19-53963359-G-C

Variant names:

• chr19-53963359-G-C
• rs775561047
• NM_031895.6:c.217G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031895.6(CACNG8):​c.217G>C​(p.Ala73Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,589,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. A73S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNG8 NM_031895.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.43
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09750965).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031895.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNG8	NM_031895.6	MANE Select	c.217G>C	p.Ala73Pro	missense	Exon 1 of 4	NP_114101.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNG8	ENST00000270458.4	TSL:1 MANE Select	c.217G>C	p.Ala73Pro	missense	Exon 1 of 4	ENSP00000270458.3	Q8WXS5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151938 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 216134 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1437824 Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2 AN XY: 715788

African (AFR) AF: 0.0000625 AC: 2 AN: 31998

American (AMR) AF: 0.00 AC: 0 AN: 43200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25622

East Asian (EAS) AF: 0.00 AC: 0 AN: 38318

South Asian (SAS) AF: 0.00 AC: 0 AN: 85072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106242

Other (OTH) AF: 0.0000168 AC: 1 AN: 59670

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151938 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74192

African (AFR) AF: 0.0000483 AC: 2 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.0
DANN	Benign	0.92
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		-2.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.021
Sift	Benign	0.071	T
Sift4G	Benign	0.29	T
Polyphen		0.055	B
Vest4		0.076
MutPred		0.33		Loss of catalytic residue at A73 (P = 0.0369)
MVP		0.085
ClinPred		0.36	T
GERP RS		-5.7
PromoterAI		-0.027	Neutral
Varity_R		0.092
gMVP		0.78

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: rs775561047; hg19: chr19-54466613;