9-128635138-A-G

Position:

• chr9-128635138-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_052844.4(DYNC2I2):​c.935T>C​(p.Phe312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYNC2I2 NM_052844.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.09

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-128635138-A-G is Pathogenic according to our data. Variant chr9-128635138-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446626.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2I2	NM_052844.4	c.935T>C	p.Phe312Ser	missense_variant	6/9	ENST00000372715.7	NP_443076.2
DYNC2I2	XM_047424057.1	c.935T>C	p.Phe312Ser	missense_variant	7/10		XP_047280013.1
DYNC2I2	XM_011519179.3	c.851T>C	p.Phe284Ser	missense_variant	7/10		XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2I2	ENST00000372715.7	c.935T>C	p.Phe312Ser	missense_variant	6/9	1	NM_052844.4	ENSP00000361800.2
DYNC2I2	ENST00000483181.1	n.528T>C		non_coding_transcript_exon_variant	2/3	2
DYNC2I2	ENST00000419989.2	n.*360T>C		downstream_gene_variant		5		ENSP00000415421.1

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

Jeune thoracic dystrophy 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	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.19	B
Vest4		0.67
MutPred		0.48		Gain of disorder (P = 0.0206);
MVP		0.59
MPC		0.51
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.59
gMVP		0.76

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: rs1554771175; hg19: chr9-131397417;