17-67030792-G-A

Variant names:

• chr17-67030792-G-A
• rs376262241
• NM_014405.4:c.772G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014405.4(CACNG4):​c.772G>A​(p.Val258Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. V258L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CACNG4 NM_014405.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.353
• Publications: 0 publications found

Genes affected

CACNG4 (HGNC:1408): (calcium voltage-gated channel auxiliary subunit gamma 4) 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. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010610759).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014405.4. 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
	CACNG4	NM_014405.4	MANE Select	c.772G>A	p.Val258Met	missense	Exon 4 of 4	NP_055220.1	Q9UBN1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNG4	ENST00000262138.4	TSL:1 MANE Select	c.772G>A	p.Val258Met	missense	Exon 4 of 4	ENSP00000262138.3	Q9UBN1
	CACNG4	ENST00000921465.1		c.631G>A	p.Val211Met	missense	Exon 3 of 3	ENSP00000591524.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000756 AC: 19 AN: 251198 AF XY: 0.0000957

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461848 Hom.: 0 Cov.: 33 AF XY: 0.0000660 AC XY: 48 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112000

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74336

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00383038), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.079
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.1
DANN	Benign	0.92
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.35
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.076
Sift	Benign	0.25	T
Sift4G	Benign	0.20	T
Polyphen		0.048	B
Vest4		0.049
MutPred		0.084		Loss of glycosylation at S259 (P = 0.0972)
MVP		0.45
MPC		0.84
ClinPred		0.020	T
GERP RS		-3.8
Varity_R		0.063
gMVP		0.20
Mutation Taster		=94/6	polymorphism

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: rs376262241; hg19: chr17-65026908;