7-143756406-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_178561.5(CTAGE6):c.1253A>G(p.Lys418Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,605,980 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (2 hom., cov: 25)
  • Exomes 𝑓: 0.00024 (58 hom.)
• Consequence: CTAGE6 NM_178561.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

Genes affected

CTAGE6 (HGNC:28644): (CTAGE family member 6) Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport; protein secretion; and vesicle cargo loading. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum exit site and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CTAGE6
• BP4: Computational evidence support a benign effect (MetaRNN=0.1862877).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTAGE6	NM_178561.5	c.1253A>G	p.Lys418Arg	missense_variant	1/1	ENST00000470691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTAGE6	ENST00000470691.2	c.1253A>G	p.Lys418Arg	missense_variant	1/1		NM_178561.5	P1
	ENST00000700950.1	n.178+12692A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000377 AC: 57 AN: 151360 Hom.: 2 Cov.: 25

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000632

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000635

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000112 AC: 28 AN: 249008 Hom.: 4 AF XY: 0.000141 AC XY: 19 AN XY: 135044

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000243 AC: 353 AN: 1454504 Hom.: 58 Cov.: 31 AF XY: 0.000240 AC XY: 174 AN XY: 723508

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000269

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000262

Gnomad4 OTH exome AF: 0.000317

GnomAD4 genome AF: 0.000376 AC: 57 AN: 151476 Hom.: 2 Cov.: 25 AF XY: 0.000365 AC XY: 27 AN XY: 74068

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.000633

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000635

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000336 Hom.: 1

ExAC AF: 0.0000994 AC: 12

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

Aug 30, 2022

The c.1253A>G (p.K418R) alteration is located in exon 1 (coding exon 1) of the CTAGE6 gene. This alteration results from a A to G substitution at nucleotide position 1253, causing the lysine (K) at amino acid position 418 to be replaced by an arginine (R). 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	0.076
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Benign	0.48
DEOGEN2	Benign	0.083	T
FATHMM_MKL	Benign	0.063	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.25	T
Polyphen		0.99	D
Vest4		0.080
MVP		0.18
GERP RS		0.11
Varity_R		0.084
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs756720979; hg19: chr7-143453499;