8-11786044-G-C

Position:

• chr8-11786044-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145043.4(NEIL2):​c.770G>C​(p.Arg257Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEIL2 NM_145043.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90

Genes affected

NEIL2 (HGNC:18956): (nei like DNA glycosylase 2) This gene encodes a member of the Fpg/Nei family of DNA glycosylases. These glycosylases initiate the first step in base excision repair by cleaving oxidatively damaged bases and introducing a DNA strand break via their abasic site lyase activity. This enzyme is primarily associated with DNA repair during transcription and acts prefentially on cytosine-derived lesions, particularly 5-hydroxyuracil and 5-hydroxycytosine. It contains an N-terminal catalytic domain, a hinge region, and a C-terminal DNA-binding domain with helix-two-turn-helix and zinc finger motifs. This enzyme interacts with the X-ray cross complementing factor 1 scaffold protein as part of a multi-protein DNA repair complex. A pseudogene of this gene has been identified. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28551406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEIL2	NM_145043.4	c.770G>C	p.Arg257Pro	missense_variant	5/5	ENST00000284503.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEIL2	ENST00000284503.7	c.770G>C	p.Arg257Pro	missense_variant	5/5	2	NM_145043.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.027	T;T;.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.85	.;.;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;L;.;.;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.036	D;D;T;D;D
Sift4G	Benign	0.075	T;T;T;T;T
Polyphen		0.94	P;P;.;.;P
Vest4		0.30
MutPred		0.53		Loss of stability (P = 0.1187);Loss of stability (P = 0.1187);.;.;Loss of stability (P = 0.1187);
MVP		0.39
MPC		0.0083
ClinPred		0.70	D
GERP RS		3.0
Varity_R		0.79
gMVP		0.80

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: rs8191664; hg19: chr8-11643553;