rs1554771066

Positions:

• chr9-128634843-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The ENST00000372715.7(DYNC2I2):​c.1060A>G​(p.Thr354Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T354M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYNC2I2 ENST00000372715.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.33

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP5: Variant 9-128634843-T-C is Pathogenic according to our data. Variant chr9-128634843-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446623.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26510602). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2I2	NM_052844.4	c.1060A>G	p.Thr354Ala	missense_variant	7/9	ENST00000372715.7	NP_443076.2
DYNC2I2	XM_047424057.1	c.1060A>G	p.Thr354Ala	missense_variant	8/10		XP_047280013.1
DYNC2I2	XM_011519179.3	c.976A>G	p.Thr326Ala	missense_variant	8/10		XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2I2	ENST00000372715.7	c.1060A>G	p.Thr354Ala	missense_variant	7/9	1	NM_052844.4	ENSP00000361800	P1
DYNC2I2	ENST00000483181.1	n.653A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.70	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.051	T
Sift4G	Benign	0.17	T
Polyphen		0.10	B
Vest4		0.49
MutPred		0.41		Gain of disorder (P = 0.3336);
MVP		0.31
MPC		0.11
ClinPred		0.25	T
GERP RS		4.0
Varity_R		0.15
gMVP		0.56

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

Other links and lift over

dbSNP: rs1554771066; hg19: chr9-131397122;