chr1-2306086-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_003036.4(SKI):c.1834C>T(p.Leu612Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,602,498 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 39 hom. )

Consequence

SKI
NM_003036.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.472

Publications

2 publications found

Variant links:

Genes affected

SKI (HGNC:10896): (SKI proto-oncogene) This gene encodes the nuclear protooncogene protein homolog of avian sarcoma viral (v-ski) oncogene. It functions as a repressor of TGF-beta signaling, and may play a role in neural tube development and muscle differentiation. [provided by RefSeq, Oct 2009]

SKI Gene-Disease associations (from GenCC):

Shprintzen-Goldberg syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, G2P, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

SKI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 1-2306086-C-T is Benign according to our data. Variant chr1-2306086-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.472 with no splicing effect.

BS2

High AC in GnomAd4 at 612 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003036.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	NM_003036.4	MANE Select	c.1834C>T	p.Leu612Leu	synonymous	Exon 6 of 7	NP_003027.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKI	ENST00000378536.5	TSL:1 MANE Select	c.1834C>T	p.Leu612Leu	synonymous	Exon 6 of 7	ENSP00000367797.4

Frequencies

GnomAD3 genomes

AF:

0.00402

AC:

612

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00633

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00354

AC:

802

AN:

226526

AF XY:

0.00360

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00782

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000786

Gnomad NFE exome

AF:

0.00549

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00593

AC:

8600

AN:

1450134

Hom.:

Cov.:

AF XY:

0.00577

AC XY:

4153

AN XY:

720290

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33388

American (AMR)

AF:

0.00307

AC:

131

AN:

42718

Ashkenazi Jewish (ASJ)

AF:

0.00794

AC:

205

AN:

25824

East Asian (EAS)

AF:

0.0000510

AC:

AN:

39252

South Asian (SAS)

AF:

0.000511

AC:

AN:

84122

European-Finnish (FIN)

AF:

0.00131

AC:

AN:

51132

Middle Eastern (MID)

AF:

0.00540

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00701

AC:

7766

AN:

1107932

Other (OTH)

AF:

0.00535

AC:

321

AN:

60020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

509

1018

1526

2035

2544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

300

600

900

1200

1500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00402

AC:

612

AN:

152364

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

273

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41594

American (AMR)

AF:

0.00496

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00634

AC:

431

AN:

68028

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00593

Hom.:

Bravo

AF:

0.00396

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

May 29, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu612Leu in exon 6 of SKI: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.6% (54/8578) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35833638).

Jun 08, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 24, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BP7

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SKI: BP4, BP7, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Shprintzen-Goldberg syndrome

Benign:2

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Mar 04, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

7.3

(source)

DANN

Benign

0.92

PhyloP100

0.47

Mutation Taster

=100/0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over