rs141875736

chr11-65720319-CCTT-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PM4_Supporting BP6_Very_Strong BA1

The NM_032193.4(RNASEH2C):c.268_270del(p.Lys90del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,614,274 control chromosomes in the GnomAD database, including 354 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (308 hom.)
• Consequence: RNASEH2C NM_032193.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.855

Genes affected

RNASEH2C (HGNC:24116): (ribonuclease H2 subunit C) This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PM1: In a chain Ribonuclease H2 subunit C (size 163) in uniprot entity RNH2C_HUMAN there are 23 pathogenic changes around while only 3 benign (88%) in NM_032193.4
• PM4: Nonframeshift variant in NON repetitive region in NM_032193.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 11-65720319-CCTT-C is Benign according to our data. Variant chr11-65720319-CCTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 305363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-65720319-CCTT-C is described in Lovd as [Benign]. Variant chr11-65720319-CCTT-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2C	NM_032193.4	c.268_270del	p.Lys90del	inframe_deletion	2/4	ENST00000308418.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2C	ENST00000308418.10	c.268_270del	p.Lys90del	inframe_deletion	2/4	1	NM_032193.4	P1

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 779 AN: 152266 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.00475

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0108 AC: 2727 AN: 251488 Hom.: 206 AF XY: 0.00983 AC XY: 1336 AN XY: 135918

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00392 AC: 5733 AN: 1461890 Hom.: 308 AF XY: 0.00385 AC XY: 2797 AN XY: 727244

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.00351

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000353

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.00510 AC: 777 AN: 152384 Hom.: 46 Cov.: 32 AF XY: 0.00609 AC XY: 454 AN XY: 74510

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.00496

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.00609

Asia WGS AF: 0.0410 AC: 142 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 22, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aicardi Goutieres syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs141875736; hg19: chr11-65487790;