9-128633958-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM1PM2PM5BP4_Strong

The NM_052844.4(DYNC2I2):c.1397A>G(p.Gln466Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q466P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DYNC2I2
NM_052844.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.372

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a repeat WD 4 (size 40) in uniprot entity DC2I2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_052844.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-128633958-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 446624.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.05199626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I2	NM_052844.4 link	c.1397A>G	p.Gln466Arg	missense_variant	Exon 9 of 9	ENST00000372715.7	NP_443076.2	Q96EX3
DYNC2I2	XM_047424057.1 link	c.1397A>G	p.Gln466Arg	missense_variant	Exon 10 of 10		XP_047280013.1
DYNC2I2	XM_011519179.3 link	c.1313A>G	p.Gln438Arg	missense_variant	Exon 10 of 10		XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2I2	ENST00000372715.7 link	c.1397A>G	p.Gln466Arg	missense_variant	Exon 9 of 9	1	NM_052844.4	ENSP00000361800.2		Q96EX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460716

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726660

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.030

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.58

M_CAP

Benign

0.014

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

PhyloP100

0.37

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.74

REVEL

Benign

0.019

Sift

Benign

0.54

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.092

MutPred

0.32

Loss of ubiquitination at K467 (P = 0.0289);

MVP

0.18

MPC

0.11

ClinPred

0.16

GERP RS

0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.052

gMVP

0.26

Mutation Taster

=96/4

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over