chr2-105337597-G-A

Variant names:

• chr2-105337597-G-A
• rs142827498
• NM_024093.3:c.10G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024093.3(C2orf49):​c.10G>A​(p.Asp4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,613,194 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: C2orf49 NM_024093.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 3 publications found

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]

C2orf49-DT (HGNC:55178): (C2orf49 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059092343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2orf49	NM_024093.3	c.10G>A	p.Asp4Asn	missense_variant	Exon 1 of 4	ENST00000258457.7	NP_076998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2orf49	ENST00000258457.7	c.10G>A	p.Asp4Asn	missense_variant	Exon 1 of 4	1	NM_024093.3	ENSP00000258457.2

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152046 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000410 AC: 101 AN: 246150 AF XY: 0.000432

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00662

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000199 AC: 291 AN: 1461148 Hom.: 1 Cov.: 44 AF XY: 0.000205 AC XY: 149 AN XY: 726900

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00574 AC: 150 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52814

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.0000737 AC: 82 AN: 1111970

Other (OTH) AF: 0.000464 AC: 28 AN: 60368

GnomAD4 genome AF: 0.000283 AC: 43 AN: 152046 Hom.: 0 Cov.: 30 AF XY: 0.000337 AC XY: 25 AN XY: 74284

African (AFR) AF: 0.0000242 AC: 1 AN: 41378

American (AMR) AF: 0.000328 AC: 5 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68004

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000470 Hom.: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000256 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10G>A (p.D4N) alteration is located in exon 1 (coding exon 1) of the C2orf49 gene. This alteration results from a G to A substitution at nucleotide position 10, causing the aspartic acid (D) at amino acid position 4 to be replaced by an asparagine (N). 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	0.24
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;.
PhyloP100		1.2
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.11
Sift	Benign	0.13	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.069	B;.
Vest4		0.077
MVP		0.47
MPC		0.15
ClinPred		0.077	T
GERP RS		2.7
PromoterAI		-0.069	Neutral
Varity_R		0.079
gMVP		0.25
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs142827498; hg19: chr2-105954054;