NM_032193.4:c.268_270delAAG

Variant names:

• chr11-65720319-CCTT-C
• rs141875736
• NM_032193.4:c.268_270delAAG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_032193.4(RNASEH2C):​c.268_270delAAG​(p.Lys90del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.855
• Publications: 5 publications found

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]

RNASEH2C Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 305363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032193.4. 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
	RNASEH2C	NM_032193.4	MANE Select	c.268_270delAAG	p.Lys90del	conservative_inframe_deletion	Exon 2 of 4	NP_115569.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2C	ENST00000308418.10	TSL:1 MANE Select	c.268_270delAAG	p.Lys90del	conservative_inframe_deletion	Exon 2 of 4	ENSP00000308193.5
	RNASEH2C	ENST00000527610.1	TSL:2	c.268_270delAAG	p.Lys90del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000432897.1
	RNASEH2C	ENST00000886953.1		c.268_270delAAG	p.Lys90del	conservative_inframe_deletion	Exon 2 of 4	ENSP00000557012.1

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

GnomAD2 exomes AF: 0.0108 AC: 2727 AN: 251488 AF XY: 0.00983

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 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

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26136

East Asian (EAS) AF: 0.117 AC: 4641 AN: 39700

South Asian (SAS) AF: 0.00351 AC: 303 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000353 AC: 392 AN: 1112012

Other (OTH) AF: 0.00477 AC: 288 AN: 60396

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

African (AFR) AF: 0.00101 AC: 42 AN: 41604

American (AMR) AF: 0.000849 AC: 13 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.129 AC: 669 AN: 5170

South Asian (SAS) AF: 0.00496 AC: 24 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68040

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Aicardi-Goutieres syndrome 3 (2)
-	-	2	not specified (2)
-	-	1	Aicardi Goutieres syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs141875736; hg19: chr11-65487790; COSMIC: COSV100383827; COSMIC: COSV100383827;