chr11-65720698-A-G

Variant names:

• chr11-65720698-A-G
• rs376140250
• NM_032193.4:c.61T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032193.4(RNASEH2C):​c.61T>C​(p.Leu21Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,594,188 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: RNASEH2C NM_032193.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.61
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-65720698-A-G is Benign according to our data. Variant chr11-65720698-A-G is described in ClinVar as Benign. ClinVar VariationId is 305367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000592 (90/152092) while in subpopulation SAS AF = 0.0181 (87/4804). AF 95% confidence interval is 0.015. There are 1 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 25 AD,AR gene

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.61T>C	p.Leu21Leu	synonymous	Exon 1 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.61T>C	p.Leu21Leu	synonymous	Exon 1 of 4	ENSP00000308193.5
	RNASEH2C	ENST00000527610.1	TSL:2	c.61T>C	p.Leu21Leu	synonymous	Exon 1 of 3	ENSP00000432897.1
	RNASEH2C	ENST00000886953.1		c.61T>C	p.Leu21Leu	synonymous	Exon 1 of 4	ENSP00000557012.1

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 151976 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00224 AC: 478 AN: 213318 AF XY: 0.00313

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000106

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.00113 AC: 1635 AN: 1442096 Hom.: 25 Cov.: 32 AF XY: 0.00166 AC XY: 1188 AN XY: 716778

African (AFR) AF: 0.00 AC: 0 AN: 33064

American (AMR) AF: 0.0000230 AC: 1 AN: 43518

Ashkenazi Jewish (ASJ) AF: 0.0000774 AC: 2 AN: 25842

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38674

South Asian (SAS) AF: 0.0177 AC: 1489 AN: 84214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46004

Middle Eastern (MID) AF: 0.000198 AC: 1 AN: 5048

European-Non Finnish (NFE) AF: 0.0000597 AC: 66 AN: 1106108

Other (OTH) AF: 0.00126 AC: 75 AN: 59624

GnomAD4 genome AF: 0.000592 AC: 90 AN: 152092 Hom.: 1 Cov.: 32 AF XY: 0.000793 AC XY: 59 AN XY: 74388

African (AFR) AF: 0.0000241 AC: 1 AN: 41498

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.0181 AC: 87 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000162

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.60
PhyloP100		1.6
PromoterAI		-0.058	Neutral
Mutation Taster		=297/3	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: rs376140250; hg19: chr11-65488169;