chr6-131708917-T-C

Variant names:

• chr6-131708917-T-C
• rs77624986
• NM_001145659.1:c.2101A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001145659.1(CTAGE9):​c.2101A>G​(p.Ile701Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,605,820 control chromosomes in the GnomAD database, including 10 homozygotes. 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: 𝑓 0.00054 (1 hom., cov: 22)
  • Exomes 𝑓: 0.00053 (9 hom.)
• Consequence: CTAGE9 NM_001145659.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.250
• Publications: 8 publications found

Genes affected

CTAGE9 (HGNC:37275): (CTAGE family member 9) 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]

ENPP3 (HGNC:3358): (ectonucleotide pyrophosphatase/phosphodiesterase 3) The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015788108).
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTAGE9	NM_001145659.1	c.2101A>G	p.Ile701Val	missense_variant	Exon 1 of 1	ENST00000314099.10	NP_001139131.1
ENPP3	NM_005021.5	c.1413-9755T>C		intron_variant	Intron 15 of 24	ENST00000357639.8	NP_005012.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTAGE9	ENST00000314099.10	c.2101A>G	p.Ile701Val	missense_variant	Exon 1 of 1	6	NM_001145659.1	ENSP00000395587.2
ENPP3	ENST00000357639.8	c.1413-9755T>C		intron_variant	Intron 15 of 24	1	NM_005021.5	ENSP00000350265.3
ENPP3	ENST00000414305.5	c.1413-9755T>C		intron_variant	Intron 16 of 25	1		ENSP00000406261.1
ENPP3	ENST00000358229.6	c.1413-9755T>C		intron_variant	Intron 15 of 23	1		ENSP00000350964.5

Frequencies

GnomAD3 genomes AF: 0.000537 AC: 78 AN: 145262 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.000496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000878

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000430

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000609

Gnomad OTH AF: 0.000999

GnomAD2 exomes AF: 0.000368 AC: 91 AN: 247586 AF XY: 0.000364

Gnomad AFR exome AF: 0.000627

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000571

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000531 AC: 776 AN: 1460450 Hom.: 9 Cov.: 34 AF XY: 0.000484 AC XY: 352 AN XY: 726566

African (AFR) AF: 0.000399 AC: 13 AN: 32608

American (AMR) AF: 0.000515 AC: 23 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86194

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000871 AC: 5 AN: 5738

European-Non Finnish (NFE) AF: 0.000608 AC: 676 AN: 1111684

Other (OTH) AF: 0.000531 AC: 32 AN: 60300

GnomAD4 genome AF: 0.000537 AC: 78 AN: 145370 Hom.: 1 Cov.: 22 AF XY: 0.000464 AC XY: 33 AN XY: 71050

African (AFR) AF: 0.000494 AC: 18 AN: 36406

American (AMR) AF: 0.000877 AC: 13 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5008

South Asian (SAS) AF: 0.000431 AC: 2 AN: 4644

European-Finnish (FIN) AF: 0.0000953 AC: 1 AN: 10494

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000609 AC: 41 AN: 67362

Other (OTH) AF: 0.000988 AC: 2 AN: 2024

Alfa AF: 0.000395 Hom.: 0

ExAC AF: 0.000327 AC: 39

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2101A>G (p.I701V) alteration is located in exon 1 (coding exon 1) of the CTAGE9 gene. This alteration results from a A to G substitution at nucleotide position 2101, causing the isoleucine (I) at amino acid position 701 to be replaced by a valine (V). 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	0.069
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.93
DANN	Benign	0.46
DEOGEN2	Benign	0.00035	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.41	T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.80	N
PhyloP100		-0.25
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.031
Sift	Benign	0.82	T
Sift4G	Benign	0.88	T
Polyphen		0.0010	B
Vest4		0.023
MVP		0.014
ClinPred		0.0049	T
Varity_R		0.34
gMVP		0.044
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs77624986; hg19: chr6-132030057; COSMIC: COSV58418112;