rs2341097

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_175875.5(SIX5):c.2077G>A(p.Val693Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,612,970 control chromosomes in the GnomAD database, including 97,361 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8345 hom., cov: 33)

Exomes 𝑓: 0.35 ( 89016 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0790

Publications

47 publications found

Variant links:

Genes affected

SIX5 (HGNC:10891): (SIX homeobox 5) The protein encoded by this gene is a homeodomain-containing transcription factor that appears to function in the regulation of organogenesis. This gene is located downstream of the dystrophia myotonica-protein kinase gene. Mutations in this gene are a cause of branchiootorenal syndrome type 2. [provided by RefSeq, Jul 2009]

SIX5 Gene-Disease associations (from GenCC):

branchiootorenal syndrome 2
Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
branchio-oto-renal syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

SIX5 links:

ENSG00000259605 (HGNC:):

ENSG00000259605 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041387975).

BP6

Variant 19-45765644-C-T is Benign according to our data. Variant chr19-45765644-C-T is described in ClinVar as Benign. ClinVar VariationId is 262913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5 link	c.2077G>A	p.Val693Met	missense_variant	Exon 3 of 3	ENST00000317578.7	NP_787071.3	Q8N196

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIX5	ENST00000317578.7 link	c.2077G>A	p.Val693Met	missense_variant	Exon 3 of 3	1	NM_175875.5	ENSP00000316842.4	Q8N196
ENSG00000259605	ENST00000559756.1 link	n.860C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
SIX5	ENST00000560160.1 link	c.*287G>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000453239.2	H0YLK1
SIX5	ENST00000560168.1 link	c.*1503G>A		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes

AF:

0.329

AC:

49969

AN:

151972

Hom.:

8344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.313

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.415

Gnomad EAS

AF:

0.266

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.319

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.358

Gnomad OTH

AF:

0.319

GnomAD2 exomes

AF:

0.320

AC:

79957

AN:

250156

AF XY:

0.323

show subpopulations

Gnomad AFR exome

AF:

0.314

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.424

Gnomad EAS exome

AF:

0.284

Gnomad FIN exome

AF:

0.319

Gnomad NFE exome

AF:

0.357

Gnomad OTH exome

AF:

0.338

GnomAD4 exome

AF:

0.345

AC:

504731

AN:

1460880

Hom.:

89016

Cov.:

AF XY:

0.345

AC XY:

251012

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.308

AC:

10326

AN:

33478

American (AMR)

AF:

0.218

AC:

9765

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.418

AC:

10929

AN:

26124

East Asian (EAS)

AF:

0.218

AC:

8664

AN:

39698

South Asian (SAS)

AF:

0.293

AC:

25281

AN:

86256

European-Finnish (FIN)

AF:

0.314

AC:

16464

AN:

52498

Middle Eastern (MID)

AF:

0.382

AC:

2201

AN:

5768

European-Non Finnish (NFE)

AF:

0.360

AC:

399973

AN:

1111956

Other (OTH)

AF:

0.350

AC:

21128

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

22688

45376

68063

90751

113439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12608

25216

37824

50432

63040

<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:

0.329

AC:

49984

AN:

152090

Hom.:

8345

Cov.:

AF XY:

0.323

AC XY:

24007

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.313

AC:

12970

AN:

41466

American (AMR)

AF:

0.262

AC:

4013

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

1440

AN:

3466

East Asian (EAS)

AF:

0.266

AC:

1370

AN:

5158

South Asian (SAS)

AF:

0.289

AC:

1393

AN:

4826

European-Finnish (FIN)

AF:

0.319

AC:

3384

AN:

10592

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.358

AC:

24361

AN:

67964

Other (OTH)

AF:

0.316

AC:

668

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1717

3434

5151

6868

8585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.343

Hom.:

8388

Bravo

AF:

0.323

TwinsUK

AF:

0.362

AC:

1341

ALSPAC

AF:

0.352

AC:

1355

ESP6500AA

AF:

0.305

AC:

1342

ESP6500EA

AF:

0.364

AC:

3127

ExAC

AF:

0.319

AC:

38720

Asia WGS

AF:

0.285

AC:

991

AN:

3478

EpiCase

AF:

0.371

EpiControl

AF:

0.375

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 09, 2017

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Branchiootorenal syndrome 2

Benign:3

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.81

.;T;T

MetaRNN

Benign

0.0041

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;.

PhyloP100

-0.079

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.27

.;N;.

REVEL

Benign

0.23

Sift

Benign

0.032

.;D;.

Sift4G

Benign

0.10

.;T;T

Polyphen

0.63

P;P;.

Vest4

0.27, 0.068

MPC

0.13

ClinPred

0.018

GERP RS

3.1

Varity_R

0.083

gMVP

0.067

Mutation Taster

=98/2

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