NM_015307.2:c.1304C>T

Variant names:

• chr15-29123655-G-A
• rs2045492597
• NM_015307.2:c.1304C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_015307.2(ENTREP2):​c.1304C>T​(p.Ala435Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,545,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ENTREP2 NM_015307.2 missense, splice_region
• Scores: Splicing: ADA: 0.00007885
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84
• Publications: 0 publications found

Genes affected

ENTREP2 (HGNC:29075): (endosomal transmembrane epsin interactor 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039042503).
• BP6: Variant 15-29123655-G-A is Benign according to our data. Variant chr15-29123655-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3089190.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTREP2	NM_015307.2	c.1304C>T	p.Ala435Val	missense_variant, splice_region_variant	Exon 11 of 11	ENST00000261275.5	NP_056122.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTREP2	ENST00000261275.5	c.1304C>T	p.Ala435Val	missense_variant, splice_region_variant	Exon 11 of 11	5	NM_015307.2	ENSP00000261275.4
ENTREP2	ENST00000560021.1	n.1040C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 8	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393114 Hom.: 0 Cov.: 35 AF XY: 0.00000146 AC XY: 1 AN XY: 686098

African (AFR) AF: 0.00 AC: 0 AN: 31332

American (AMR) AF: 0.00 AC: 0 AN: 35118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25010

East Asian (EAS) AF: 0.00 AC: 0 AN: 35532

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074598

Other (OTH) AF: 0.00 AC: 0 AN: 57682

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 07, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.2
DANN	Benign	0.30
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.3	N
PhyloP100		1.8
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.046
Sift	Benign	0.61	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.038
MutPred		0.16		Loss of relative solvent accessibility (P = 0.0186);
MVP		0.014
ClinPred		0.017	T
GERP RS		0.14
Varity_R		0.025
gMVP		0.064
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.044
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

Other links and lift over

dbSNP: rs2045492597; hg19: chr15-29415858;