9-128634837-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_052844.4(DYNC2I2):c.1066G>A(p.Gly356Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00292 in 1,613,514 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 21 hom. )

Consequence

DYNC2I2
NM_052844.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.64

Publications

5 publications found

Variant links:

Genes affected

DYNC2I2 (HGNC:28296): (dynein 2 intermediate chain 2) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Defects in this gene are a cause of short-rib thoracic dysplasia 11 with or without polydactyly. [provided by RefSeq, Mar 2014]

DYNC2I2 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 11 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Verma-Naumoff type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYNC2I2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_052844.4

BP4

Computational evidence support a benign effect (MetaRNN=0.014472216).

BP6

Variant 9-128634837-C-T is Benign according to our data. Variant chr9-128634837-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00266 (405/152354) while in subpopulation SAS AF = 0.00786 (38/4832). AF 95% confidence interval is 0.00589. There are 1 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I2	NM_052844.4 link	c.1066G>A	p.Gly356Ser	missense_variant	Exon 7 of 9	ENST00000372715.7	NP_443076.2	Q96EX3
DYNC2I2	XM_047424057.1 link	c.1066G>A	p.Gly356Ser	missense_variant	Exon 8 of 10		XP_047280013.1
DYNC2I2	XM_011519179.3 link	c.982G>A	p.Gly328Ser	missense_variant	Exon 8 of 10		XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2I2	ENST00000372715.7 link	c.1066G>A	p.Gly356Ser	missense_variant	Exon 7 of 9	1	NM_052844.4	ENSP00000361800.2		Q96EX3
DYNC2I2	ENST00000483181.1 link	n.659G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00266

AC:

405

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00786

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00367

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00395

AC:

985

AN:

249316

AF XY:

0.00436

show subpopulations

Gnomad AFR exome

AF:

0.000376

Gnomad AMR exome

AF:

0.00464

Gnomad ASJ exome

AF:

0.00888

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00150

Gnomad NFE exome

AF:

0.00384

Gnomad OTH exome

AF:

0.00558

GnomAD4 exome

AF:

0.00295

AC:

4308

AN:

1461160

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

2412

AN XY:

726892

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33476

American (AMR)

AF:

0.00430

AC:

192

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00827

AC:

216

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39690

South Asian (SAS)

AF:

0.00829

AC:

715

AN:

86232

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

52908

Middle Eastern (MID)

AF:

0.00801

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00253

AC:

2810

AN:

1111916

Other (OTH)

AF:

0.00389

AC:

235

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

268

536

803

1071

1339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00266

AC:

405

AN:

152354

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

197

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41586

American (AMR)

AF:

0.00196

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00786

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00368

AC:

250

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00336

Hom.:

Bravo

AF:

0.00241

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00406

AC:

493

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 07, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32576942) -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DYNC2I2: BS2 -

Short-rib thoracic dysplasia 11 with or without polydactyly

Benign:2

May 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DYNC2I2-related disorder

Benign:1

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

Eigen

Benign

0.075

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PhyloP100

5.6

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.1

REVEL

Benign

0.18

Sift

Benign

0.16

Sift4G

Benign

0.19

Polyphen

0.40

Vest4

0.64

MVP

0.35

MPC

0.35

ClinPred

0.017

GERP RS

5.2

Varity_R

0.29

gMVP

0.66

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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