chr2-17759972-T-C

Variant names:

• chr2-17759972-T-C
• NM_001130009.3:c.29T>C

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.29T>C​(p.Leu10Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GEN1 NM_001130009.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

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.29T>C	p.Leu10Ser	missense	Exon 2 of 14	NP_001123481.3	Q17RS7
	GEN1	NM_182625.5		c.29T>C	p.Leu10Ser	missense	Exon 2 of 14	NP_872431.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEN1	ENST00000381254.7	TSL:5 MANE Select	c.29T>C	p.Leu10Ser	missense	Exon 2 of 14	ENSP00000370653.2	Q17RS7
	GEN1	ENST00000317402.11	TSL:2	c.29T>C	p.Leu10Ser	missense	Exon 2 of 14	ENSP00000318977.7	Q17RS7
	GEN1	ENST00000862145.1		c.29T>C	p.Leu10Ser	missense	Exon 2 of 14	ENSP00000532204.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.87		Gain of disorder (P = 0.0161)
MVP		0.80
MPC		0.27
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.89
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

hg19: chr2-17941239;