NM_018051.5:c.2395A>G

Variant names:

Variant summary

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

The NM_018051.5(DYNC2I1):c.2395A>G(p.Ile799Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,613,352 control chromosomes in the GnomAD database, including 282 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I799I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.024 ( 149 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 133 hom. )

Consequence

DYNC2I1
NM_018051.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.723

Publications

5 publications found

Variant links:

Genes affected

DYNC2I1 (HGNC:21862): (dynein 2 intermediate chain 1) 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) and may facilitate the 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. The encoded protein contains four WD repeats and may play a role in the formation of cilia. Mutations in this gene have been associated with short-rib polydactyly and Jeune syndromes. [provided by RefSeq, Mar 2014]

DYNC2I1 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 8 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, 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

DYNC2I1 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=0.0022461414).

BP6

Variant 7-158926425-A-G is Benign according to our data. Variant chr7-158926425-A-G is described in ClinVar as Benign. ClinVar VariationId is 474627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0818 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018051.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYNC2I1	NM_018051.5	MANE Select	c.2395A>G	p.Ile799Val	missense	Exon 19 of 25	NP_060521.4
DYNC2I1	NM_001350914.2		c.2257A>G	p.Ile753Val	missense	Exon 19 of 25	NP_001337843.1
DYNC2I1	NM_001350915.2		c.1822A>G	p.Ile608Val	missense	Exon 18 of 24	NP_001337844.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DYNC2I1	ENST00000407559.8	TSL:1 MANE Select	c.2395A>G	p.Ile799Val	missense	Exon 19 of 25	ENSP00000384290.3	Q8WVS4
DYNC2I1	ENST00000444851.5	TSL:1	n.1553A>G		non_coding_transcript_exon	Exon 14 of 20	ENSP00000392608.1	H7C022
DYNC2I1	ENST00000860814.1		c.2470A>G	p.Ile824Val	missense	Exon 20 of 26	ENSP00000530873.1

Frequencies

GnomAD3 genomes

AF:

0.0241

AC:

3674

AN:

152218

Hom.:

148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0843

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.00564

AC:

1399

AN:

247850

AF XY:

0.00430

show subpopulations

Gnomad AFR exome

AF:

0.0828

Gnomad AMR exome

AF:

0.00303

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00183

GnomAD4 exome

AF:

0.00228

AC:

3325

AN:

1461016

Hom.:

133

Cov.:

AF XY:

0.00196

AC XY:

1423

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.0837

AC:

2795

AN:

33396

American (AMR)

AF:

0.00350

AC:

156

AN:

44584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000174

AC:

AN:

86132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1111606

Other (OTH)

AF:

0.00486

AC:

293

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

165

330

496

661

826

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:

0.0242

AC:

3679

AN:

152336

Hom.:

149

Cov.:

AF XY:

0.0235

AC XY:

1751

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0842

AC:

3498

AN:

41568

American (AMR)

AF:

0.00856

AC:

131

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68036

Other (OTH)

AF:

0.0175

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

169

338

506

675

844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.00861

Hom.:

Bravo

AF:

0.0259

ESP6500AA

AF:

0.0772

AC:

296

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00689

AC:

833

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Short-rib thoracic dysplasia 8 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.5

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0087

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

0.72

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.96

REVEL

Benign

0.15

Sift

Benign

0.034

Sift4G

Uncertain

0.026

Polyphen

0.10

Vest4

0.22

MVP

0.35

MPC

0.068

ClinPred

0.0038

GERP RS

-0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.037

gMVP

0.18

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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