chr19-45368655-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000400.4(ERCC2):​c.335G>A​(p.Arg112His) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R112C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.16
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 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-45368656-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1028731.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.918
PP5
Variant 19-45368655-C-T is Pathogenic according to our data. Variant chr19-45368655-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ERCC2NM_000400.4 linkuse as main transcriptc.335G>A p.Arg112His missense_variant 5/23 ENST00000391945.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ERCC2ENST00000391945.10 linkuse as main transcriptc.335G>A p.Arg112His missense_variant 5/231 NM_000400.4 P1P18074-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251144
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135762
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461188
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
726910
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000971
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 28, 2022In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25795128, 12820975, 25897079, 15494306, 18817897, 23232694, 23800062, 12458209, 25431422, 25605938, 10667598, 27982466, 27085493, 27262611, 7920640, 9758621, 25620205, 23221806, 30580289, 33670118) -
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 10, 2023This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 112 of the ERCC2 protein (p.Arg112His). This variant is present in population databases (rs121913020, gnomAD 0.008%). This missense change has been observed in individuals with trichothiodystrophy (PMID: 7920640, 9758621). This variant is also known as a G to A mutation at position 413. ClinVar contains an entry for this variant (Variation ID: 16784). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ERCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ERCC2 function (PMID: 25431422). For these reasons, this variant has been classified as Pathogenic. -
Xeroderma pigmentosum, group D Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 15, 2001- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJan 28, 2022- -
Cerebrooculofacioskeletal syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 16, 2024- -
Trichothiodystrophy 1, photosensitive Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 15, 2001- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.77
D;D;D;.;.;D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Pathogenic
4.4
H;.;.;.;.;.
MutationTaster
Benign
1.0
A;A;A;A;A
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-4.5
D;D;.;D;.;.
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;D;.;D;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D;.;D
Polyphen
1.0
D;D;.;.;.;.
Vest4
0.96
MVP
0.98
MPC
0.89
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs121913020; hg19: chr19-45871913; COSMIC: COSV104544608; COSMIC: COSV104544608; API