rs300168

Positions:

• chr2-17781183-A-C
• chr2-17781183-A-G
• chr2-17781183-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130009.3(GEN1):​c.1971A>C​(p.Glu657Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GEN1 NM_001130009.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08165926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GEN1	NM_001130009.3	c.1971A>C	p.Glu657Asp	missense_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>C	p.Glu657Asp	missense_variant	14/14	5	NM_001130009.3	ENSP00000370653.2
GEN1	ENST00000317402.11	c.1971A>C	p.Glu657Asp	missense_variant	14/14	2		ENSP00000318977.7
SMC6	ENST00000402989.5	c.-6+6632T>G		intron_variant		2		ENSP00000384539.1
SMC6	ENST00000428868.1	c.-6+6632T>G		intron_variant		4		ENSP00000415352.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0050	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.62	.;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.040
Sift	Benign	0.034	D;D
Sift4G	Benign	0.33	T;T
Polyphen		0.028	B;B
Vest4		0.061
MutPred		0.094		Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);
MVP		0.41
MPC		0.034
ClinPred		0.15	T
GERP RS		1.6
Varity_R		0.062
gMVP		0.12

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;