chr9-95876045-C-T

Variant names:

• chr9-95876045-C-T
• rs776425022
• NM_020207.7:c.7C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020207.7(ERCC6L2):​c.7C>T​(p.Pro3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,436,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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. P3Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ERCC6L2 NM_020207.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319
• Publications: 0 publications found

Genes affected

ERCC6L2 (HGNC:26922): (ERCC excision repair 6 like 2) This gene encodes a member of the Snf2 family of helicase-like proteins. The encoded protein may play a role in DNA repair and mitochondrial function. Mutations in this gene have been associated with bone marrow failure syndrome 2. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Apr 2014]

ERCC6L2-AS1 (HGNC:27858): (ERCC6L2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033759236).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020207.7. 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
	ERCC6L2	NM_020207.7	MANE Select	c.7C>T	p.Pro3Ser	missense	Exon 1 of 19	NP_064592.3	Q5T890-1
	ERCC6L2	NM_001375291.1		c.7C>T	p.Pro3Ser	missense	Exon 1 of 19	NP_001362220.1
	ERCC6L2	NM_001375292.1		c.7C>T	p.Pro3Ser	missense	Exon 1 of 19	NP_001362221.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6L2	ENST00000653738.2	MANE Select	c.7C>T	p.Pro3Ser	missense	Exon 1 of 19	ENSP00000499221.2	Q5T890-1
	ERCC6L2	ENST00000288985.13	TSL:1	c.7C>T	p.Pro3Ser	missense	Exon 1 of 14	ENSP00000288985.8	A0A5F9UKL4
	ERCC6L2-AS1	ENST00000412446.6	TSL:1	n.5G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1436444 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712442

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32786

American (AMR) AF: 0.00 AC: 0 AN: 41826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25556

East Asian (EAS) AF: 0.00 AC: 0 AN: 37962

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100396

Other (OTH) AF: 0.00 AC: 0 AN: 59356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.90
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.71	T
PhyloP100		-0.32
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.19
Sift	Benign	0.092	T
Sift4G	Benign	0.092	T
Vest4		0.11
MutPred		0.14		Gain of phosphorylation at P14 (P = 0.0031)
MVP		0.22
MPC		0.22
ClinPred		0.12	T
GERP RS		-1.9
PromoterAI		-0.037	Neutral
gMVP		0.18
Mutation Taster		=100/0	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: rs776425022; hg19: chr9-98638327; COSMIC: COSV56634219; COSMIC: COSV56634219;