2-68046346-C-A

Position:

• chr2-68046346-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_173177.3(C1D):​c.203G>T​(p.Trp68Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: C1D NM_173177.3 missense, splice_region
• Scores: Splicing: ADA: 0.9530
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

Genes affected

C1D (HGNC:29911): (C1D nuclear receptor corepressor) The protein encoded by this gene is a DNA binding and apoptosis-inducing protein and is localized in the nucleus. It is also a Rac3-interacting protein which acts as a corepressor for the thyroid hormone receptor. This protein is thought to regulate TRAX/Translin complex formation. Alternate splicing results in multiple transcript variants that encode the same protein. Multiple pseudogenes of this gene are found on chromosome 10.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1D	NM_173177.3	c.203G>T	p.Trp68Leu	missense_variant, splice_region_variant	3/5	ENST00000410067.8	NP_775269.1
C1D	NM_001190263.2	c.203G>T	p.Trp68Leu	missense_variant, splice_region_variant	4/6		NP_001177192.1
C1D	NM_001190265.2	c.203G>T	p.Trp68Leu	missense_variant, splice_region_variant	4/6		NP_001177194.1
C1D	NM_006333.4	c.203G>T	p.Trp68Leu	missense_variant, splice_region_variant	3/5		NP_006324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1D	ENST00000410067.8	c.203G>T	p.Trp68Leu	missense_variant, splice_region_variant	3/5	1	NM_173177.3	ENSP00000386468	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.203G>T (p.W68L) alteration is located in exon 4 (coding exon 2) of the C1D gene. This alteration results from a G to T substitution at nucleotide position 203, causing the tryptophan (W) at amino acid position 68 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;T;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;.;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.3	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-12	D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.99	D;.;D;D
Vest4		0.70
MutPred		0.71		Gain of phosphorylation at Y70 (P = 0.1706);.;Gain of phosphorylation at Y70 (P = 0.1706);Gain of phosphorylation at Y70 (P = 0.1706);
MVP		0.59
MPC		0.21
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.80
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-68273478;