6-7329855-C-G

Variant names:

• chr6-7329855-C-G
• rs1467809427
• NM_001170692.2:c.2472G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001170692.2(CAGE1):​c.2472G>C​(p.Met824Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000308 in 1,300,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CAGE1 NM_001170692.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

Genes affected

CAGE1 (HGNC:21622): (cancer antigen 1)

SSR1 (HGNC:11323): (signal sequence receptor subunit 1) The signal sequence receptor (SSR) is a glycosylated endoplasmic reticulum (ER) membrane receptor associated with protein translocation across the ER membrane. The SSR consists of 2 subunits, a 34-kD glycoprotein encoded by this gene and a 22-kD glycoprotein. This gene generates several mRNA species as a result of complex alternative polyadenylation. This gene is unusual in that it utilizes arrays of polyA signal sequences that are mostly non-canonical. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1469732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAGE1	NM_001170692.2	c.2472G>C	p.Met824Ile	missense_variant	Exon 13 of 14	ENST00000502583.6	NP_001164163.1
CAGE1	NM_001170693.2	c.2367G>C	p.Met789Ile	missense_variant	Exon 12 of 13		NP_001164164.1
CAGE1	NM_205864.3	c.1878G>C	p.Met626Ile	missense_variant	Exon 10 of 11		NP_995586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAGE1	ENST00000502583.6	c.2472G>C	p.Met824Ile	missense_variant	Exon 13 of 14	5	NM_001170692.2	ENSP00000425493.1
CAGE1	ENST00000338150.8	c.2367G>C	p.Met789Ile	missense_variant	Exon 12 of 13	2		ENSP00000338107.4
CAGE1	ENST00000379918.8	c.2406G>C	p.Met802Ile	missense_variant	Exon 13 of 14	5		ENSP00000369250.4
CAGE1	ENST00000512086.5	c.2286G>C	p.Met762Ile	missense_variant	Exon 11 of 12	5		ENSP00000427583.1
CAGE1	ENST00000296742.11	c.1878G>C	p.Met626Ile	missense_variant	Exon 10 of 11	1		ENSP00000296742.7
CAGE1	ENST00000442019.6	n.*1738G>C		non_coding_transcript_exon_variant	Exon 13 of 14	1		ENSP00000391746.2
CAGE1	ENST00000458291.6	n.*424G>C		non_coding_transcript_exon_variant	Exon 13 of 14	1		ENSP00000390644.2
CAGE1	ENST00000442019.6	n.*1738G>C		3_prime_UTR_variant	Exon 13 of 14	1		ENSP00000391746.2
CAGE1	ENST00000458291.6	n.*424G>C		3_prime_UTR_variant	Exon 13 of 14	1		ENSP00000390644.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000244 AC: 5 AN: 205218 Hom.: 0 AF XY: 0.00000912 AC XY: 1 AN XY: 109596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000308 AC: 4 AN: 1300004 Hom.: 0 Cov.: 19 AF XY: 0.00000154 AC XY: 1 AN XY: 649794

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000102

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2472G>C (p.M824I) alteration is located in exon 13 (coding exon 12) of the CAGE1 gene. This alteration results from a G to C substitution at nucleotide position 2472, causing the methionine (M) at amino acid position 824 to be replaced by an isoleucine (I). 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	Uncertain	0.46
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0026	.;.;.;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.67	T;T;T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	.;.;.;L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.64	N;N;N;N;N
REVEL	Benign	0.051
Sift	Uncertain	0.028	D;D;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.21, 0.43	.;.;.;B;B
Vest4		0.24
MutPred		0.19		.;.;.;Loss of MoRF binding (P = 0.1085);.;
MVP		0.32
MPC		0.15
ClinPred		0.20	T
GERP RS		4.7
Varity_R		0.33
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1467809427; hg19: chr6-7330088;