chr8-11779849-G-T

Variant names:

• chr8-11779849-G-T
• rs935317810
• NM_145043.4:c.390G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_145043.4(NEIL2):​c.390G>T​(p.Trp130Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEIL2 NM_145043.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145043.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL2	NM_145043.4	MANE Select	c.390G>T	p.Trp130Cys	missense	Exon 3 of 5	NP_659480.1	Q969S2-1
	NEIL2	NM_001135746.3		c.390G>T	p.Trp130Cys	missense	Exon 3 of 5	NP_001129218.1	Q969S2-1
	NEIL2	NM_001349442.2		c.390G>T	p.Trp130Cys	missense	Exon 4 of 6	NP_001336371.1	Q969S2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEIL2	ENST00000284503.7	TSL:2 MANE Select	c.390G>T	p.Trp130Cys	missense	Exon 3 of 5	ENSP00000284503.6	Q969S2-1
	NEIL2	ENST00000436750.7	TSL:1	c.390G>T	p.Trp130Cys	missense	Exon 3 of 5	ENSP00000394023.2	Q969S2-1
	NEIL2	ENST00000455213.6	TSL:5	c.390G>T	p.Trp130Cys	missense	Exon 4 of 6	ENSP00000397538.2	Q969S2-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.78		Loss of MoRF binding (P = 0.0181)
MVP		0.36
MPC		0.012
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.48
gMVP		0.71
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs935317810; hg19: chr8-11637358;