chr2-17759914-T-G

Variant names:

• chr2-17759914-T-G
• rs199871757
• NM_001130009.3:c.-15-15T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001130009.3(GEN1):​c.-15-15T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,608,706 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 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: GEN1 NM_001130009.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.692
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 2-17759914-T-G is Benign according to our data. Variant chr2-17759914-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 223816.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 53 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130009.3. 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
	GEN1	NM_001130009.3	MANE Select	c.-15-15T>G		intron	N/A	NP_001123481.3	Q17RS7
	GEN1	NM_182625.5		c.-15-15T>G		intron	N/A	NP_872431.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEN1	ENST00000381254.7	TSL:5 MANE Select	c.-15-15T>G		intron	N/A	ENSP00000370653.2	Q17RS7
	GEN1	ENST00000912259.1		c.-30T>G		splice_region	Exon 2 of 14	ENSP00000582318.1
	GEN1	ENST00000532257.1	TSL:4	c.-30T>G		splice_region	Exon 2 of 3	ENSP00000433180.1	E9PM30

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000607 AC: 151 AN: 248720 AF XY: 0.000714

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00393

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000356

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000345 AC: 503 AN: 1456364 Hom.: 1 Cov.: 30 AF XY: 0.000402 AC XY: 291 AN XY: 724464

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.000226 AC: 10 AN: 44278

Ashkenazi Jewish (ASJ) AF: 0.00370 AC: 96 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00169 AC: 145 AN: 85824

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53352

Middle Eastern (MID) AF: 0.00436 AC: 25 AN: 5732

European-Non Finnish (NFE) AF: 0.000158 AC: 175 AN: 1108122

Other (OTH) AF: 0.000814 AC: 49 AN: 60172

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74496

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.000457 AC: 7 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000979 Hom.: 0

Bravo AF: 0.000287

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.49		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199871757; hg19: chr2-17941181;