2-17774401-G-T

Variant names:

• chr2-17774401-G-T
• rs755927285
• NM_001130009.3:c.1202G>T

Variant summary

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

The NM_001130009.3(GEN1):​c.1202G>T​(p.Arg401Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,262 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R401Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GEN1 NM_001130009.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.38
• 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]

LOC105373449 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEN1	NM_001130009.3	c.1202G>T	p.Arg401Leu	missense_variant, splice_region_variant	Exon 11 of 14	ENST00000381254.7	NP_001123481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEN1	ENST00000381254.7	c.1202G>T	p.Arg401Leu	missense_variant, splice_region_variant	Exon 11 of 14	5	NM_001130009.3	ENSP00000370653.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445262 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 718728

African (AFR) AF: 0.00 AC: 0 AN: 32764

American (AMR) AF: 0.00 AC: 0 AN: 42862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25642

East Asian (EAS) AF: 0.00 AC: 0 AN: 39196

South Asian (SAS) AF: 0.00 AC: 0 AN: 83152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103894

Other (OTH) AF: 0.00 AC: 0 AN: 59592

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.7	M;M;.
PhyloP100		9.4
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.019	D;D;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.83
MutPred		0.49		Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);.;
MVP		0.78
MPC		0.25
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.54
gMVP		0.71
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.72		Position offset: 0

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

Other links and lift over

dbSNP: rs755927285; hg19: chr2-17955668;