rs147948835

Variant names:

• chr9-95955996-C-T
• rs147948835
• NM_020207.7:c.1930C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95955996-C-T
• chr9-95955996-C-A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_020207.7(ERCC6L2):​c.1930C>T​(p.Arg644*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,594,454 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 (★★). ClinVar reports functional evidence for this variant: "SCV003925897: Published functional studies demonstrate a damaging effect of this variant, which formed abnormal cytoplasmic aggregates and localized to autophagic vacuoles (Tummala et al., 2014)" and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: ERCC6L2 NM_020207.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.36
• Publications: 5 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 Gene-Disease associations (from GenCC):

• pancytopenia-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003925897: Published functional studies demonstrate a damaging effect of this variant, which formed abnormal cytoplasmic aggregates and localized to autophagic vacuoles (Tummala et al., 2014); PMID: 24507776, 29146883, 27185855, 37011912; SCV006325146: Functional studies have demonstrated that cells with this variant in the homozygous state do not express ERCC6L2 and form aggregates (PMID: 24507776).
• PP5: Variant 9-95955996-C-T is Pathogenic according to our data. Variant chr9-95955996-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 125449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1930C>T	p.Arg644*	stop_gained	Exon 13 of 19	NP_064592.3	Q5T890-1
	ERCC6L2	NM_001375291.1		c.1930C>T	p.Arg644*	stop_gained	Exon 13 of 19	NP_001362220.1
	ERCC6L2	NM_001375292.1		c.1930C>T	p.Arg644*	stop_gained	Exon 13 of 19	NP_001362221.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6L2	ENST00000653738.2	MANE Select	c.1930C>T	p.Arg644*	stop_gained	Exon 13 of 19	ENSP00000499221.2	Q5T890-1
	ERCC6L2	ENST00000288985.13	TSL:1	c.1930C>T	p.Arg644*	stop_gained	Exon 13 of 14	ENSP00000288985.8	A0A5F9UKL4
	ERCC6L2	ENST00000456993.7	TSL:1	n.*1112C>T		non_coding_transcript_exon	Exon 12 of 18	ENSP00000409751.2	F2Z2R4

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000160 AC: 39 AN: 243100 AF XY: 0.000137

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000948

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000287

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000288 AC: 415 AN: 1442432 Hom.: 0 Cov.: 26 AF XY: 0.000272 AC XY: 195 AN XY: 717920

African (AFR) AF: 0.00 AC: 0 AN: 32692

American (AMR) AF: 0.0000714 AC: 3 AN: 42028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25682

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39320

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83730

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.000363 AC: 399 AN: 1100534

Other (OTH) AF: 0.000151 AC: 9 AN: 59668

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74248

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000328 Hom.: 1

Bravo AF: 0.000249

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000157 AC: 19

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
3	-	-	Pancytopenia-developmental delay syndrome (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		2.4
Vest4		0.42
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=18/182	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs147948835; hg19: chr9-98718278;