Genetic Variant C1orf94:p.Thr222Ile (chr1-34197569-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001134734.2(C1orf94):c.665C>T(p.Thr222Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T222R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

C1orf94
NM_001134734.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.250

Publications

0 publications found

Variant links:

Genes affected

C1orf94 (HGNC:28250): (chromosome 1 open reading frame 94)

C1orf94 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06674901).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134734.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf94	NM_001134734.2	MANE Select	c.665C>T	p.Thr222Ile	missense	Exon 2 of 7	NP_001128206.1	Q6P1W5-1
	C1orf94	NM_032884.5		c.95C>T	p.Thr32Ile	missense	Exon 2 of 7	NP_116273.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf94	ENST00000488417.2	TSL:1 MANE Select	c.665C>T	p.Thr222Ile	missense	Exon 2 of 7	ENSP00000435634.1	Q6P1W5-1
	C1orf94	ENST00000373374.7	TSL:1	c.95C>T	p.Thr32Ile	missense	Exon 2 of 7	ENSP00000362472.3	Q6P1W5-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250974

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.52

M_CAP

Benign

0.0095

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.5

PhyloP100

0.25

PROVEAN

Benign

-1.9

REVEL

Benign

0.039

Sift

Benign

0.052

Sift4G

Benign

0.10

Polyphen

0.22

Vest4

0.11

MutPred

0.11

Loss of phosphorylation at T222 (P = 0.0305)

MVP

0.27

MPC

0.038

ClinPred

0.096

GERP RS

1.7

Varity_R

0.060

gMVP

0.096

Mutation Taster

=99/1

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over