9-128635185-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_052844.4(DYNC2I2):c.888A>G(p.Leu296Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,284 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L296L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0078 ( 4 hom., cov: 33)

Exomes 𝑓: 0.014 ( 182 hom. )

Consequence

DYNC2I2
NM_052844.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.198

Publications

3 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 9-128635185-T-C is Benign according to our data. Variant chr9-128635185-T-C is described in ClinVar as Benign. ClinVar VariationId is 474850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.198 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00783 (1192/152148) while in subpopulation NFE AF = 0.0134 (911/67974). AF 95% confidence interval is 0.0127. There are 4 homozygotes in GnomAd4. There are 551 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052844.4. 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
	DYNC2I2	NM_052844.4	MANE Select	c.888A>G	p.Leu296Leu	synonymous	Exon 6 of 9	NP_443076.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYNC2I2	ENST00000372715.7	TSL:1 MANE Select	c.888A>G	p.Leu296Leu	synonymous	Exon 6 of 9	ENSP00000361800.2
DYNC2I2	ENST00000946364.1		c.885A>G	p.Leu295Leu	synonymous	Exon 6 of 9	ENSP00000616423.1
DYNC2I2	ENST00000925011.1		c.870A>G	p.Leu290Leu	synonymous	Exon 6 of 9	ENSP00000595070.1

Frequencies

GnomAD3 genomes

AF:

0.00784

AC:

1192

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00552

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00547

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0134

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00745

AC:

1864

AN:

250062

AF XY:

0.00751

show subpopulations

Gnomad AFR exome

AF:

0.00279

Gnomad AMR exome

AF:

0.00475

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00436

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.00704

GnomAD4 exome

AF:

0.0140

AC:

20460

AN:

1461136

Hom.:

182

Cov.:

AF XY:

0.0136

AC XY:

9851

AN XY:

726904

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

33480

American (AMR)

AF:

0.00499

AC:

223

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00413

AC:

218

AN:

52750

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0172

AC:

19111

AN:

1111960

Other (OTH)

AF:

0.0127

AC:

769

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1278

2557

3835

5114

6392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.00783

AC:

1192

AN:

152148

Hom.:

Cov.:

AF XY:

0.00741

AC XY:

551

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00299

AC:

124

AN:

41526

American (AMR)

AF:

0.00484

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00547

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0134

AC:

911

AN:

67974

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00799

Hom.:

Bravo

AF:

0.00818

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.0119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Short-rib thoracic dysplasia 11 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

8.0

(source)

DANN

Benign

0.71

PhyloP100

0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over