NM_001130009.3:c.-16+1552T>G

Variant names:

• chr2-17755897-T-G
• rs551170881
• NM_001130009.3:c.-16+1552T>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001130009.3(GEN1):​c.-16+1552T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 152,352 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: GEN1 NM_001130009.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.32

Genes affected

GEN1 (HGNC:26881): (GEN1 Holliday junction 5' flap endonuclease) This gene encodes a member of the Rad2/xeroderma pigmentosum group G nuclease family, whose members are characterized by N-terminal and internal xeroderma pigmentosum group G nuclease domains followed by helix-hairpin-helix domains and disordered C-terminal domains. The protein encoded by this gene is involved in resolution of Holliday junctions, which are intermediate four-way structures that covalently link DNA during homologous recombination and double-strand break repair. The protein resolves Holliday junctions by creating dual incisions across the junction to produce nicked duplex products that can be ligated. In addition, this protein has been found to localize to centrosomes where it has been implicated in regulation of centrosome integrity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

SMC6 (HGNC:20466): (structural maintenance of chromosomes 6) Enables ubiquitin protein ligase binding activity. Involved in several processes, including cellular senescence; positive regulation of chromosome segregation; and telomere maintenance via recombination. Located in chromosome and nuclear body. Part of Smc5-Smc6 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 2-17755897-T-G is Benign according to our data. Variant chr2-17755897-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 223806.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEN1	NM_001130009.3	c.-16+1552T>G		intron_variant	Intron 1 of 13	ENST00000381254.7	NP_001123481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEN1	ENST00000381254.7	c.-16+1552T>G		intron_variant	Intron 1 of 13	5	NM_001130009.3	ENSP00000370653.2

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000955

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74508

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000945

Bravo AF: 0.000642

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Dec 01, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.88

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: rs551170881; hg19: chr2-17937164;