6-7329865-G-A

Position:

• chr6-7329865-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001170692.2(CAGE1):​c.2462C>T​(p.Pro821Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000439 in 1,458,374 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: CAGE1 NM_001170692.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.646

Genes affected

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

SSR1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027061313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAGE1	NM_001170692.2	c.2462C>T	p.Pro821Leu	missense_variant	13/14	ENST00000502583.6	NP_001164163.1
CAGE1	NM_001170693.2	c.2357C>T	p.Pro786Leu	missense_variant	12/13		NP_001164164.1
CAGE1	NM_205864.3	c.1868C>T	p.Pro623Leu	missense_variant	10/11		NP_995586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAGE1	ENST00000502583.6	c.2462C>T	p.Pro821Leu	missense_variant	13/14	5	NM_001170692.2	ENSP00000425493.1
CAGE1	ENST00000338150.8	c.2357C>T	p.Pro786Leu	missense_variant	12/13	2		ENSP00000338107.4
CAGE1	ENST00000379918.8	c.2396C>T	p.Pro799Leu	missense_variant	13/14	5		ENSP00000369250.4
CAGE1	ENST00000512086.5	c.2276C>T	p.Pro759Leu	missense_variant	11/12	5		ENSP00000427583.1
CAGE1	ENST00000296742.11	c.1868C>T	p.Pro623Leu	missense_variant	10/11	1		ENSP00000296742.7
CAGE1	ENST00000442019.6	n.*1728C>T		non_coding_transcript_exon_variant	13/14	1		ENSP00000391746.2
CAGE1	ENST00000458291.6	n.*414C>T		non_coding_transcript_exon_variant	13/14	1		ENSP00000390644.2
CAGE1	ENST00000442019.6	n.*1728C>T		3_prime_UTR_variant	13/14	1		ENSP00000391746.2
CAGE1	ENST00000458291.6	n.*414C>T		3_prime_UTR_variant	13/14	1		ENSP00000390644.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152076 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.000128 AC: 26 AN: 202688 Hom.: 0 AF XY: 0.000129 AC XY: 14 AN XY: 108246

Gnomad AFR exome AF: 0.000162

Gnomad AMR exome AF: 0.000562

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000286

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000406 AC: 53 AN: 1306180 Hom.: 0 Cov.: 19 AF XY: 0.0000429 AC XY: 28 AN XY: 652532

Gnomad4 AFR exome AF: 0.0000652

Gnomad4 AMR exome AF: 0.000382

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000333

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152194 Hom.: 1 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74420

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000327

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: 0.0000168 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000749 AC: 9

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

Oct 29, 2021

The c.2462C>T (p.P821L) alteration is located in exon 13 (coding exon 12) of the CAGE1 gene. This alteration results from a C to T substitution at nucleotide position 2462, causing the proline (P) at amino acid position 821 to be replaced by a leucine (L). 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	Benign	0.14
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.0052	.;.;.;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.67	T;T;T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.42	.;.;.;N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N;D;D;D;D
REVEL	Benign	0.069
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		0.55	.;.;.;P;P
Vest4		0.21
MVP		0.67
MPC		0.45
ClinPred		0.060	T
GERP RS		2.9
Varity_R		0.079
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs142647100; hg19: chr6-7330098;