rs587777096

Variant names:

• chr9-128634726-C-T
• rs587777096
• NM_052844.4:c.1177G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM2 PP3_Strong PP5

The NM_052844.4(DYNC2I2):​c.1177G>A​(p.Gly393Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000943 in 1,590,442 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV003452060: Experimental studies have shown that this missense change affects WDR34 function (PMID:32576942).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G393D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: DYNC2I2 NM_052844.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 5.62
• Publications: 3 publications found

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: ClinGen, 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003452060: Experimental studies have shown that this missense change affects WDR34 function (PMID: 32576942).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 9-128634726-C-T is Pathogenic according to our data. Variant chr9-128634726-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97042.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052844.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I2	NM_052844.4	MANE Select	c.1177G>A	p.Gly393Ser	missense	Exon 7 of 9	NP_443076.2	Q96EX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I2	ENST00000372715.7	TSL:1 MANE Select	c.1177G>A	p.Gly393Ser	missense	Exon 7 of 9	ENSP00000361800.2	Q96EX3
	DYNC2I2	ENST00000946364.1		c.1174G>A	p.Gly392Ser	missense	Exon 7 of 9	ENSP00000616423.1
	DYNC2I2	ENST00000925011.1		c.1159G>A	p.Gly387Ser	missense	Exon 7 of 9	ENSP00000595070.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000143 AC: 3 AN: 209460 AF XY: 0.00000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000632

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000217

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000834 AC: 12 AN: 1438304 Hom.: 0 Cov.: 33 AF XY: 0.00000561 AC XY: 4 AN XY: 713274

African (AFR) AF: 0.0000302 AC: 1 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 40312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25508

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38694

South Asian (SAS) AF: 0.00 AC: 0 AN: 83028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000908 AC: 10 AN: 1101250

Other (OTH) AF: 0.00 AC: 0 AN: 59522

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000446 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Jeune thoracic dystrophy (2)
2	-	-	Short-rib thoracic dysplasia 11 with or without polydactyly (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.71		Loss of catalytic residue at G393 (P = 0.0111)
MVP		0.43
MPC		0.52
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.82
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777096; hg19: chr9-131397005;