9-128634842-G-A

Position:

chr9-128634842-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_052844.4(DYNC2I2):c.1061C>T(p.Thr354Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DYNC2I2
NM_052844.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.74

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 links:

DYNC2I2 (HGNC:):

DYNC2I2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

PP5

Variant 9-128634842-G-A is Pathogenic according to our data. Variant chr9-128634842-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97038.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2I2	NM_052844.4 linkuse as main transcript	c.1061C>T	p.Thr354Met	missense_variant	7/9	ENST00000372715.7	NP_443076.2	Q96EX3
DYNC2I2	XM_047424057.1 linkuse as main transcript	c.1061C>T	p.Thr354Met	missense_variant	8/10		XP_047280013.1
DYNC2I2	XM_011519179.3 linkuse as main transcript	c.977C>T	p.Thr326Met	missense_variant	8/10		XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2I2	ENST00000372715.7 linkuse as main transcript	c.1061C>T	p.Thr354Met	missense_variant	7/9	1	NM_052844.4	ENSP00000361800.2		Q96EX3
DYNC2I2	ENST00000483181.1 linkuse as main transcript	n.654C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249414

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135292

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461196

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000896

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

DYNC2I2-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 22, 2023

The DYNC2I2 c.1061C>T variant is predicted to result in the amino acid substitution p.Thr354Met. This variant was reported in the homozygous state in two cases of short-rib polydactyly syndrome and/or asphyxiating thoracic dysplasia (Huber et al. 2013. PubMed ID: 24183449; Table S1, Monies et al. 2019. PubMed ID: 31130284). Functional studies showed that this variant impacts normal protein function (Huber et al. 2013. PubMed ID: 24183449; Shak et al. 2022. PubMed ID: 36268591). This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-131397121-G-A). A different nucleotide substitution affecting the same amino acid (p.Thr354Ala) has been reported in the compound heterozygous state in one case of short-rib polydactyly syndrome (Table S2, Zhang et al. 2018. PubMed ID: 29068549). Taken together, the c.1061C>T (p.Thr354Met) variant is interpreted as likely pathogenic. -

Short-rib thoracic dysplasia 11 with or without polydactyly

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 07, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.1

REVEL

Benign

0.21

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.79

MVP

0.45

MPC

0.41

ClinPred

0.77

GERP RS

5.2

Varity_R

0.078

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over