19-45351661-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000400.4(ERCC2):​c.2251A>G​(p.Lys751Glu) 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. 16/22 in silico tools predict a benign outcome for this variant. 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. K751Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13295361).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	NM_000400.4	MANE Select	c.2251A>G	p.Lys751Glu	missense	Exon 23 of 23	NP_000391.1
	ERCC2	NM_001440355.1		c.2179A>G	p.Lys727Glu	missense	Exon 23 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.2173A>G	p.Lys725Glu	missense	Exon 22 of 22	NP_001427285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.2251A>G	p.Lys751Glu	missense	Exon 23 of 23	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.*248A>G		3_prime_UTR	Exon 22 of 22	ENSP00000375808.4
	ERCC2	ENST00000891927.1		c.2347A>G	p.Lys783Glu	missense	Exon 24 of 24	ENSP00000561986.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.41	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.87	L
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.15
Sift	Benign	0.50	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.18		Loss of methylation at K751 (P = 0.014)
MVP		0.86
MPC		0.29
ClinPred		0.065	T
GERP RS		4.3
Varity_R		0.095
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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;