rs16981869

Variant names:

• chr2-17764976-A-G
• rs16981869
• NM_001130009.3:c.428A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-17764976-A-G
• chr2-17764976-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130009.3(GEN1):​c.428A>G​(p.Asn143Ser) variant causes a missense change. The variant allele was found at a frequency of 0.105 in 1,613,922 control chromosomes in the GnomAD database, including 9,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1705 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8134 hom.)
• Consequence: GEN1 NM_001130009.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.12
• Publications: 34 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]

LOC105373449 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018734038).
• BP6: Variant 2-17764976-A-G is Benign according to our data. Variant chr2-17764976-A-G is described in ClinVar as Benign. ClinVar VariationId is 1167514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEN1	NM_001130009.3	c.428A>G	p.Asn143Ser	missense_variant	Exon 4 of 14	ENST00000381254.7	NP_001123481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEN1	ENST00000381254.7	c.428A>G	p.Asn143Ser	missense_variant	Exon 4 of 14	5	NM_001130009.3	ENSP00000370653.2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20666 AN: 152058 Hom.: 1703 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0366

Gnomad SAS AF: 0.0960

Gnomad FIN AF: 0.0813

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.100 AC: 25221 AN: 251450 AF XY: 0.100

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.0740

Gnomad ASJ exome AF: 0.0994

Gnomad EAS exome AF: 0.0348

Gnomad FIN exome AF: 0.0784

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0992

GnomAD4 exome AF: 0.102 AC: 149228 AN: 1461746 Hom.: 8134 Cov.: 31 AF XY: 0.102 AC XY: 73986 AN XY: 727192

African (AFR) AF: 0.241 AC: 8075 AN: 33466

American (AMR) AF: 0.0774 AC: 3459 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0990 AC: 2587 AN: 26132

East Asian (EAS) AF: 0.0429 AC: 1701 AN: 39696

South Asian (SAS) AF: 0.0971 AC: 8378 AN: 86248

European-Finnish (FIN) AF: 0.0794 AC: 4244 AN: 53418

Middle Eastern (MID) AF: 0.108 AC: 625 AN: 5768

European-Non Finnish (NFE) AF: 0.102 AC: 113865 AN: 1111910

Other (OTH) AF: 0.104 AC: 6294 AN: 60390

GnomAD4 genome AF: 0.136 AC: 20690 AN: 152176 Hom.: 1705 Cov.: 32 AF XY: 0.134 AC XY: 9955 AN XY: 74384

African (AFR) AF: 0.234 AC: 9726 AN: 41496

American (AMR) AF: 0.102 AC: 1559 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3470

East Asian (EAS) AF: 0.0367 AC: 190 AN: 5184

South Asian (SAS) AF: 0.0969 AC: 467 AN: 4818

European-Finnish (FIN) AF: 0.0813 AC: 861 AN: 10596

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7143 AN: 68008

Other (OTH) AF: 0.122 AC: 258 AN: 2112

Alfa AF: 0.112 Hom.: 4673

Bravo AF: 0.141

TwinsUK AF: 0.103 AC: 382

ALSPAC AF: 0.0937 AC: 361

ESP6500AA AF: 0.229 AC: 1008

ESP6500EA AF: 0.103 AC: 883

ExAC AF: 0.104 AC: 12682

Asia WGS AF: 0.0700 AC: 242 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.105

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	.;D
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		7.1
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.29
Sift	Benign	0.030	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.81	P;P
Vest4		0.20
MPC		0.21
ClinPred		0.089	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.33
Mutation Taster		=87/13	polymorphism (auto)

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: rs16981869; hg19: chr2-17946243; COSMIC: COSV58057028; COSMIC: COSV58057028;