19-45352249-G-A

Position:

• chr19-45352249-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The ENST00000391945.10(ERCC2):​c.2150C>T​(p.Ala717Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A717G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC2 ENST00000391945.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.00

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000391945.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-45352249-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 134102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.2150C>T	p.Ala717Val	missense_variant	22/23	ENST00000391945.10	NP_000391.1
ERCC2	XM_011526611.3	c.2072C>T	p.Ala691Val	missense_variant	21/22		XP_011524913.1
ERCC2	XR_001753633.3	n.2183C>T		non_coding_transcript_exon_variant	22/24
ERCC2	XR_007066680.1	n.2105C>T		non_coding_transcript_exon_variant	21/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.2150C>T	p.Ala717Val	missense_variant	22/23	1	NM_000400.4	ENSP00000375809	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.4	N;N;.
REVEL	Uncertain	0.55
Sift	Benign	0.031	D;D;.
Sift4G	Benign	0.10	T;T;T
Polyphen		0.061	B;B;.
Vest4		0.55
MutPred		0.49		Gain of methylation at K718 (P = 0.0424);.;.;
MVP		0.86
MPC		0.21
ClinPred		0.88	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144564120; hg19: chr19-45855507;