2-44942680-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_005413.4(SIX3):c.576C>T(p.Arg192Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,601,098 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 84 hom., cov: 32)

Exomes 𝑓: 0.021 ( 371 hom. )

Consequence

SIX3
NM_005413.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.691

Publications

6 publications found

Variant links:

Genes affected

SIX3 (HGNC:10889): (SIX homeobox 3) This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]

SIX3 links:

ENSG00000225156 (HGNC:):

ENSG00000225156 links:

SIX3-AS1 (HGNC:40532): (SIX3 antisense RNA 1)

SIX3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 2-44942680-C-T is Benign according to our data. Variant chr2-44942680-C-T is described in ClinVar as Benign. ClinVar VariationId is 65500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.691 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0275 (4188/152284) while in subpopulation AFR AF = 0.0491 (2041/41550). AF 95% confidence interval is 0.0473. There are 84 homozygotes in GnomAd4. There are 2008 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 84 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX3	NM_005413.4 link	c.576C>T	p.Arg192Arg	synonymous_variant	Exon 1 of 2	ENST00000260653.5	NP_005404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SIX3	ENST00000260653.5 link	c.576C>T	p.Arg192Arg	synonymous_variant	Exon 1 of 2	1	NM_005413.4	ENSP00000260653.3
ENSG00000225156	ENST00000760330.1 link	n.135+8304C>T		intron_variant	Intron 1 of 1
SIX3-AS1	ENST00000760560.1 link	n.389-1847G>A		intron_variant	Intron 1 of 1
SIX3-AS1	ENST00000760561.1 link	n.365+1707G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0273

AC:

4160

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.0363

Gnomad EAS

AF:

0.00290

Gnomad SAS

AF:

0.0241

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0272

GnomAD2 exomes

AF:

0.0200

AC:

4740

AN:

236806

AF XY:

0.0206

show subpopulations

Gnomad AFR exome

AF:

0.0486

Gnomad AMR exome

AF:

0.0135

Gnomad ASJ exome

AF:

0.0312

Gnomad EAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0248

GnomAD4 exome

AF:

0.0206

AC:

29832

AN:

1448814

Hom.:

371

Cov.:

AF XY:

0.0208

AC XY:

14976

AN XY:

721110

show subpopulations

African (AFR)

AF:

0.0519

AC:

1738

AN:

33458

American (AMR)

AF:

0.0145

AC:

646

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

775

AN:

26110

East Asian (EAS)

AF:

0.00166

AC:

AN:

39656

South Asian (SAS)

AF:

0.0233

AC:

2010

AN:

86154

European-Finnish (FIN)

AF:

0.0123

AC:

507

AN:

41194

Middle Eastern (MID)

AF:

0.0220

AC:

127

AN:

5764

European-Non Finnish (NFE)

AF:

0.0203

AC:

22613

AN:

1111576

Other (OTH)

AF:

0.0224

AC:

1350

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1890

3779

5669

7558

9448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.0275

AC:

4188

AN:

152284

Hom.:

Cov.:

AF XY:

0.0270

AC XY:

2008

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0491

AC:

2041

AN:

41550

American (AMR)

AF:

0.0172

AC:

263

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0363

AC:

126

AN:

3470

East Asian (EAS)

AF:

0.00290

AC:

AN:

5168

South Asian (SAS)

AF:

0.0241

AC:

116

AN:

4816

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0211

AC:

1438

AN:

68032

Other (OTH)

AF:

0.0269

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

210

421

631

842

1052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0129

Hom.:

Bravo

AF:

0.0278

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32022405) -

Oct 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SIX3: BP4, BP7, BS1, BS2 -

Oct 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Holoprosencephaly 2

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 29, 2013

GeneReviews

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Schizencephaly;C1834877:Holoprosencephaly 2

Benign:1

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.69

Mutation Taster

=93/7

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over