19-45352226-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_000400.4(ERCC2):​c.2173G>A​(p.Ala725Thr) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A725P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ERCC2
NM_000400.4 missense

Scores

11
7
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.13
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000400.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-45352226-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.824
PP5
Variant 19-45352226-C-T is Pathogenic according to our data. Variant chr19-45352226-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2428974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERCC2NM_000400.4 linkc.2173G>A p.Ala725Thr missense_variant Exon 22 of 23 ENST00000391945.10 NP_000391.1 P18074-1
ERCC2XM_011526611.3 linkc.2095G>A p.Ala699Thr missense_variant Exon 21 of 22 XP_011524913.1
ERCC2XR_001753633.3 linkn.2206G>A non_coding_transcript_exon_variant Exon 22 of 24
ERCC2XR_007066680.1 linkn.2128G>A non_coding_transcript_exon_variant Exon 21 of 23

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERCC2ENST00000391945.10 linkc.2173G>A p.Ala725Thr missense_variant Exon 22 of 23 1 NM_000400.4 ENSP00000375809.4 P18074-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cerebrooculofacioskeletal syndrome 2 Pathogenic:1
Jul 12, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Feb 03, 2023
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22617342, 23232694, 20633800) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;T;T
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.82
D;D;D
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Pathogenic
3.2
M;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.2
D;D;.
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0010
D;D;.
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
0.96
P;D;.
Vest4
0.73
MutPred
0.55
Gain of phosphorylation at A725 (P = 0.0605);.;.;
MVP
0.96
MPC
0.74
ClinPred
0.99
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.81
gMVP
0.67

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913018; hg19: chr19-45855484; COSMIC: COSV67269220; COSMIC: COSV67269220; API