chr2-105337669-C-T

Position:

• chr2-105337669-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024093.3(C2orf49):​c.82C>T​(p.Leu28Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000704 in 141,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000070 (0 hom., cov: 28)
• Consequence: C2orf49 NM_024093.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

Genes affected

C2orf49 (HGNC:28772): (chromosome 2 open reading frame 49) Predicted to be involved in embryonic morphogenesis. Located in nucleus. Part of tRNA-splicing ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31876493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C2orf49	NM_024093.3	c.82C>T	p.Leu28Phe	missense_variant	1/4	ENST00000258457.7	NP_076998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C2orf49	ENST00000258457.7	c.82C>T	p.Leu28Phe	missense_variant	1/4	1	NM_024093.3	ENSP00000258457	P1
C2orf49	ENST00000410049.1	c.82C>T	p.Leu28Phe	missense_variant	1/5	1		ENSP00000386361

Frequencies

GnomAD3 genomes AF: 0.00000704 AC: 1 AN: 141960 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 44

GnomAD4 genome AF: 0.00000704 AC: 1 AN: 141960 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 68730

Gnomad4 AFR AF: 0.0000257

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Aug 09, 2021

The c.82C>T (p.L28F) alteration is located in exon 1 (coding exon 1) of the C2orf49 gene. This alteration results from a C to T substitution at nucleotide position 82, causing the leucine (L) at amino acid position 28 to be replaced by a phenylalanine (F). 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	Benign	0.29
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.99	D;D;D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.059	T;T
Polyphen		0.99	D;.
Vest4		0.38
MutPred		0.28		Loss of stability (P = 0.059);Loss of stability (P = 0.059);
MVP		0.49
MPC		0.21
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.65
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs991080602; hg19: chr2-105954126;