17-42987313-A-C

Variant names:

• chr17-42987313-A-C
• rs766280856
• NM_173079.5:c.556A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173079.5(RUNDC1):​c.556A>C​(p.Ile186Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNDC1 NM_173079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.03

Genes affected

RUNDC1 (HGNC:25418): (RUN domain containing 1) This gene encodes a protein that contains a RUN (RPIP8, UNC-14 and NESCA) domain and a coiled coil domain. The encoded protein may negatively regulate p53 transcriptional activity. This gene is a potential candidate gene for predisposition to glioma in humans. [provided by RefSeq, May 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNDC1	NM_173079.5	c.556A>C	p.Ile186Leu	missense_variant	Exon 2 of 5	ENST00000361677.6	NP_775102.3
RUNDC1	NM_001321381.3	c.562A>C	p.Ile188Leu	missense_variant	Exon 3 of 6		NP_001308310.2
RUNDC1	NM_001394222.1	c.556A>C	p.Ile186Leu	missense_variant	Exon 2 of 5		NP_001381151.1
RUNDC1	XM_005257078.5	c.562A>C	p.Ile188Leu	missense_variant	Exon 3 of 6		XP_005257135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNDC1	ENST00000361677.6	c.556A>C	p.Ile186Leu	missense_variant	Exon 2 of 5	1	NM_173079.5	ENSP00000354622.1
RUNDC1	ENST00000589705.1	c.550A>C	p.Ile184Leu	missense_variant	Exon 2 of 4	5		ENSP00000467953.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.556A>C (p.I186L) alteration is located in exon 2 (coding exon 2) of the RUNDC1 gene. This alteration results from a A to C substitution at nucleotide position 556, causing the isoleucine (I) at amino acid position 186 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.75
MutPred		0.30		Loss of methylation at K183 (P = 0.048);
MVP		0.78
MPC		0.63
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.54

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

Publications

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Other links and lift over

dbSNP: rs766280856; hg19: chr17-41139330;