11-65720698-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_032193.4(RNASEH2C):​c.61T>G​(p.Leu21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNASEH2C NM_032193.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a chain Ribonuclease H2 subunit C (size 163) in uniprot entity RNH2C_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_032193.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20483056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2C	NM_032193.4	c.61T>G	p.Leu21Val	missense_variant	Exon 1 of 4	ENST00000308418.10	NP_115569.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2C	ENST00000308418.10	c.61T>G	p.Leu21Val	missense_variant	Exon 1 of 4	1	NM_032193.4	ENSP00000308193.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.71	.;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		1.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.62	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.059	T;D
Sift4G	Benign	0.25	T;T
Polyphen		0.68	P;.
Vest4		0.14
MutPred		0.44		Gain of MoRF binding (P = 0.0822);Gain of MoRF binding (P = 0.0822);
MVP		0.10
MPC		0.92
ClinPred		0.53	D
GERP RS		2.4
PromoterAI		-0.068	Neutral
Varity_R		0.18
gMVP		0.69
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;