6-7334088-A-C

Position:

• chr6-7334088-A-C

Variant summary

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

The NM_001170692.2(CAGE1):​c.2372T>G​(p.Leu791Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000238 in 1,513,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: CAGE1 NM_001170692.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51

Genes affected

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

SSR1 (HGNC:):

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
CAGE1	NM_001170692.2	c.2372T>G	p.Leu791Trp	missense_variant, splice_region_variant	12/14	ENST00000502583.6	NP_001164163.1
CAGE1	NM_001170693.2	c.2267T>G	p.Leu756Trp	missense_variant, splice_region_variant	11/13		NP_001164164.1
CAGE1	NM_205864.3	c.1778T>G	p.Leu593Trp	missense_variant, splice_region_variant	9/11		NP_995586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAGE1	ENST00000502583.6	c.2372T>G	p.Leu791Trp	missense_variant, splice_region_variant	12/14	5	NM_001170692.2	ENSP00000425493.1
CAGE1	ENST00000338150.8	c.2267T>G	p.Leu756Trp	missense_variant, splice_region_variant	11/13	2		ENSP00000338107.4
CAGE1	ENST00000379918.8	c.2306T>G	p.Leu769Trp	missense_variant, splice_region_variant	12/14	5		ENSP00000369250.4
CAGE1	ENST00000512086.5	c.2186T>G	p.Leu729Trp	missense_variant, splice_region_variant	10/12	5		ENSP00000427583.1
CAGE1	ENST00000296742.11	c.1778T>G	p.Leu593Trp	missense_variant, splice_region_variant	9/11	1		ENSP00000296742.7
CAGE1	ENST00000442019.6	n.*1638T>G		splice_region_variant, non_coding_transcript_exon_variant	12/14	1		ENSP00000391746.2
CAGE1	ENST00000458291.6	n.*324T>G		splice_region_variant, non_coding_transcript_exon_variant	12/14	1		ENSP00000390644.2
CAGE1	ENST00000442019.6	n.*1638T>G		3_prime_UTR_variant	12/14	1		ENSP00000391746.2
CAGE1	ENST00000458291.6	n.*324T>G		3_prime_UTR_variant	12/14	1		ENSP00000390644.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 31

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000655 AC: 1 AN: 152684 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 80472

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000163

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000242 AC: 33 AN: 1361628 Hom.: 0 Cov.: 24 AF XY: 0.0000238 AC XY: 16 AN XY: 673274

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: 0.0000314

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

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

Jul 30, 2024

The c.2372T>G (p.L791W) alteration is located in exon 12 (coding exon 11) of the CAGE1 gene. This alteration results from a T to G substitution at nucleotide position 2372, causing the leucine (L) at amino acid position 791 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	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	26
DANN	Benign	0.97
DEOGEN2	Benign	0.024	.;.;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.72	T;T;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.1	.;.;.;L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N;D;N;N;D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;T
Polyphen		1.0	.;.;.;D;D
Vest4		0.71
MutPred		0.30		.;.;.;Gain of MoRF binding (P = 0.0516);.;
MVP		0.77
MPC		0.58
ClinPred		0.92	D
GERP RS		4.6
Varity_R		0.18
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1211224176; hg19: chr6-7334321;