Genetic Variant DYNC2I1:p.Arg489Arg (chr7-158911554-C-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_018051.5(DYNC2I1):c.1465C>A(p.Arg489Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DYNC2I1
NM_018051.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.79

Publications

3 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.2).

BP7

Synonymous conserved (PhyloP=2.79 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I1	NM_018051.5 link	c.1465C>A	p.Arg489Arg	synonymous_variant	Exon 12 of 25	ENST00000407559.8	NP_060521.4	Q8WVS4A0A140VK66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DYNC2I1	ENST00000407559.8 link	c.1465C>A	p.Arg489Arg	synonymous_variant	Exon 12 of 25	1	NM_018051.5	ENSP00000384290.3	Q8WVS4
DYNC2I1	ENST00000444851.5 link	n.796C>A		non_coding_transcript_exon_variant	Exon 8 of 20	1		ENSP00000392608.1	H7C022
DYNC2I1	ENST00000467220.1 link	n.3264C>A		non_coding_transcript_exon_variant	Exon 7 of 20	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247238

AF XY:

0.00000746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459710

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725992

African (AFR)

AF:

0.00

AC:

AN:

33388

American (AMR)

AF:

0.00

AC:

AN:

44354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

85592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111222

Other (OTH)

AF:

0.00

AC:

AN:

60292

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.000196

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

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:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over