2-17781183-A-G

Position:

• chr2-17781183-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130009.3(GEN1):​c.1971A>G​(p.Glu657Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,612,856 control chromosomes in the GnomAD database, including 246,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (19084 hom., cov: 33)
  • Exomes 𝑓: 0.55 (227683 hom.)
• Consequence: GEN1 NM_001130009.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.707

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]

LOC105373449 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-17781183-A-G is Benign according to our data. Variant chr2-17781183-A-G is described in ClinVar as [Benign]. Clinvar id is 1169877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.707 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEN1	NM_001130009.3	c.1971A>G	p.Glu657Glu	synonymous_variant	14/14	ENST00000381254.7	NP_001123481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GEN1	ENST00000381254.7	c.1971A>G	p.Glu657Glu	synonymous_variant	14/14	5	NM_001130009.3	ENSP00000370653.2
GEN1	ENST00000317402.11	c.1971A>G	p.Glu657Glu	synonymous_variant	14/14	2		ENSP00000318977.7
SMC6	ENST00000402989.5	c.-6+6632T>C		intron_variant		2		ENSP00000384539.1
SMC6	ENST00000428868.1	c.-6+6632T>C		intron_variant		4		ENSP00000415352.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71325 AN: 151950 Hom.: 19073 Cov.: 33

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.496

GnomAD3 exomes AF: 0.589 AC: 147641 AN: 250642 Hom.: 47303 AF XY: 0.596 AC XY: 80692 AN XY: 135464

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.747

Gnomad ASJ exome AF: 0.547

Gnomad EAS exome AF: 0.923

Gnomad SAS exome AF: 0.768

Gnomad FIN exome AF: 0.491

Gnomad NFE exome AF: 0.515

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.548 AC: 800356 AN: 1460788 Hom.: 227683 Cov.: 41 AF XY: 0.554 AC XY: 402608 AN XY: 726754

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.730

Gnomad4 ASJ exome AF: 0.543

Gnomad4 EAS exome AF: 0.903

Gnomad4 SAS exome AF: 0.764

Gnomad4 FIN exome AF: 0.493

Gnomad4 NFE exome AF: 0.523

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.469 AC: 71365 AN: 152068 Hom.: 19084 Cov.: 33 AF XY: 0.479 AC XY: 35588 AN XY: 74352

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.618

Gnomad4 ASJ AF: 0.551

Gnomad4 EAS AF: 0.919

Gnomad4 SAS AF: 0.778

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.514

Gnomad4 OTH AF: 0.501

Alfa AF: 0.515 Hom.: 33739

Bravo AF: 0.466

Asia WGS AF: 0.809 AC: 2810 AN: 3478

EpiCase AF: 0.525

EpiControl AF: 0.526

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.3
DANN	Benign	0.79

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: rs300168; hg19: chr2-17962450; COSMIC: COSV58057416; COSMIC: COSV58057416;