chr19-45351661-T-G

Variant names:

• chr19-45351661-T-G
• rs13181
• NM_000400.4:c.2251A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000400.4(ERCC2):​c.2251A>C​(p.Lys751Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,613,486 control chromosomes in the GnomAD database, including 103,967 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K751R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (8237 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95730 hom.)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 1.27
• Publications: 1076 publications found

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]

KLC3 (HGNC:20717): (kinesin light chain 3) This gene encodes a member of the kinesin light chain gene family. Kinesins are molecular motors involved in the transport of cargo along microtubules, and are composed of two kinesin heavy chain (KHC) and two kinesin light chain (KLC) molecules. KLCs are thought to typically be involved in binding cargo and regulating kinesin activity. In the rat, a protein similar to this gene product is expressed in post-meiotic spermatids, where it associates with structural components of sperm tails and mitochondria. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044302046).
• BP6: Variant 19-45351661-T-G is Benign according to our data. Variant chr19-45351661-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000400.4. 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
	ERCC2	NM_000400.4	MANE Select	c.2251A>C	p.Lys751Gln	missense	Exon 23 of 23	NP_000391.1
	ERCC2	NM_001440355.1		c.2179A>C	p.Lys727Gln	missense	Exon 23 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.2173A>C	p.Lys725Gln	missense	Exon 22 of 22	NP_001427285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.2251A>C	p.Lys751Gln	missense	Exon 23 of 23	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.*248A>C		3_prime_UTR	Exon 22 of 22	ENSP00000375808.4
	ERCC2	ENST00000891927.1		c.2347A>C	p.Lys783Gln	missense	Exon 24 of 24	ENSP00000561986.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47995 AN: 151946 Hom.: 8232 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.0729

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.323

GnomAD2 exomes AF: 0.325 AC: 81291 AN: 250340 AF XY: 0.336

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.0755

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.355 AC: 519083 AN: 1461422 Hom.: 95730 Cov.: 46 AF XY: 0.357 AC XY: 259873 AN XY: 727020

African (AFR) AF: 0.224 AC: 7500 AN: 33478

American (AMR) AF: 0.206 AC: 9214 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 10842 AN: 26134

East Asian (EAS) AF: 0.0556 AC: 2209 AN: 39698

South Asian (SAS) AF: 0.376 AC: 32451 AN: 86252

European-Finnish (FIN) AF: 0.417 AC: 22204 AN: 53246

Middle Eastern (MID) AF: 0.397 AC: 2290 AN: 5768

European-Non Finnish (NFE) AF: 0.370 AC: 411677 AN: 1111742

Other (OTH) AF: 0.343 AC: 20696 AN: 60382

GnomAD4 genome AF: 0.316 AC: 48019 AN: 152064 Hom.: 8237 Cov.: 32 AF XY: 0.316 AC XY: 23521 AN XY: 74338

African (AFR) AF: 0.232 AC: 9607 AN: 41462

American (AMR) AF: 0.253 AC: 3875 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1384 AN: 3470

East Asian (EAS) AF: 0.0725 AC: 375 AN: 5170

South Asian (SAS) AF: 0.363 AC: 1750 AN: 4822

European-Finnish (FIN) AF: 0.418 AC: 4421 AN: 10570

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.374 AC: 25439 AN: 67962

Other (OTH) AF: 0.320 AC: 675 AN: 2112

Alfa AF: 0.350 Hom.: 44391

Bravo AF: 0.295

TwinsUK AF: 0.385 AC: 1426

ALSPAC AF: 0.363 AC: 1399

ESP6500AA AF: 0.235 AC: 1037

ESP6500EA AF: 0.372 AC: 3203

ExAC AF: 0.330 AC: 40010

Asia WGS AF: 0.185 AC: 649 AN: 3478

EpiCase AF: 0.382

EpiControl AF: 0.380

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	3	not provided (3)
-	-	2	Xeroderma pigmentosum, group D (2)
-	-	1	Cerebrooculofacioskeletal syndrome 2 (1)
-	-	1	Trichothiodystrophy 1, photosensitive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.63
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
PhyloP100		1.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.20
Sift	Benign	0.58	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.073
MPC		0.22
ClinPred		0.0018	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13181; hg19: chr19-45854919; COSMIC: COSV67266431; COSMIC: COSV67266431;