chr13-50953991-T-C

Variant names:

• chr13-50953991-T-C
• rs76413207
• NM_024570.4:c.822+6T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_024570.4(RNASEH2B):​c.822+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,563,916 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (10 hom.)
• Consequence: RNASEH2B NM_024570.4 splice_region, intron
• Scores: Splicing: ADA: 0.7763
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.33
• Publications: 0 publications found

Genes affected

RNASEH2B (HGNC:25671): (ribonuclease H2 subunit B) RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits (B and C) and specifically degrades the RNA of RNA:DNA hybrids. The protein encoded by this gene is the non-catalytic B subunit of RNase H2, which is thought to play a role in DNA replication. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Aicardi-Goutieres syndrome type 2 (AGS2). [provided by RefSeq, Nov 2008]

RNASEH2B Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 2

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 13-50953991-T-C is Benign according to our data. Variant chr13-50953991-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00655 (998/152272) while in subpopulation AFR AF = 0.0229 (951/41554). AF 95% confidence interval is 0.0217. There are 14 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024570.4. 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
	RNASEH2B	NM_024570.4	MANE Select	c.822+6T>C		splice_region intron	N/A	NP_078846.2
	RNASEH2B	NM_001411023.1		c.741+4486T>C		intron	N/A	NP_001397952.1
	RNASEH2B	NM_001142279.2		c.741+4486T>C		intron	N/A	NP_001135751.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2B	ENST00000336617.8	TSL:1 MANE Select	c.822+6T>C		splice_region intron	N/A	ENSP00000337623.2
	RNASEH2B	ENST00000616907.2	TSL:3	c.828T>C	p.Cys276Cys	synonymous	Exon 10 of 10	ENSP00000482701.2
	RNASEH2B	ENST00000646960.1		c.822+6T>C		splice_region intron	N/A	ENSP00000496481.1

Frequencies

GnomAD3 genomes AF: 0.00657 AC: 1000 AN: 152154 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00186 AC: 465 AN: 249436 AF XY: 0.00132

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.000692 AC: 977 AN: 1411644 Hom.: 10 Cov.: 25 AF XY: 0.000603 AC XY: 425 AN XY: 705100

African (AFR) AF: 0.0254 AC: 819 AN: 32298

American (AMR) AF: 0.00126 AC: 56 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39448

South Asian (SAS) AF: 0.0000470 AC: 4 AN: 85192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5690

European-Non Finnish (NFE) AF: 0.0000244 AC: 26 AN: 1066596

Other (OTH) AF: 0.00121 AC: 71 AN: 58704

GnomAD4 genome AF: 0.00655 AC: 998 AN: 152272 Hom.: 14 Cov.: 32 AF XY: 0.00653 AC XY: 486 AN XY: 74448

African (AFR) AF: 0.0229 AC: 951 AN: 41554

American (AMR) AF: 0.00203 AC: 31 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00343 Hom.: 1

Bravo AF: 0.00783

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.96
PhyloP100		2.3
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.78
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.060		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: rs76413207; hg19: chr13-51528127;