9-128636354-C-T

Variant names:

• chr9-128636354-C-T
• rs61744155
• NM_052844.4:c.630G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_052844.4(DYNC2I2):​c.630G>A​(p.Pro210Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,607,802 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (61 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (68 hom.)
• Consequence: DYNC2I2 NM_052844.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.09
• Publications: 2 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 9-128636354-C-T is Benign according to our data. Variant chr9-128636354-C-T is described in ClinVar as Benign. ClinVar VariationId is 474849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

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.630G>A	p.Pro210Pro	synonymous	Exon 4 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.630G>A	p.Pro210Pro	synonymous	Exon 4 of 9	ENSP00000361800.2	Q96EX3
	DYNC2I2	ENST00000946364.1		c.630G>A	p.Pro210Pro	synonymous	Exon 4 of 9	ENSP00000616423.1
	DYNC2I2	ENST00000925011.1		c.630G>A	p.Pro210Pro	synonymous	Exon 4 of 9	ENSP00000595070.1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2456 AN: 152172 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00427 AC: 1016 AN: 238032 AF XY: 0.00298

Gnomad AFR exome AF: 0.0585

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00189

GnomAD4 exome AF: 0.00180 AC: 2616 AN: 1455512 Hom.: 68 Cov.: 31 AF XY: 0.00156 AC XY: 1132 AN XY: 723666

African (AFR) AF: 0.0609 AC: 2034 AN: 33390

American (AMR) AF: 0.00280 AC: 123 AN: 43946

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.0000822 AC: 7 AN: 85132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52340

Middle Eastern (MID) AF: 0.00592 AC: 34 AN: 5746

European-Non Finnish (NFE) AF: 0.000189 AC: 210 AN: 1109446

Other (OTH) AF: 0.00344 AC: 207 AN: 60094

GnomAD4 genome AF: 0.0161 AC: 2458 AN: 152290 Hom.: 61 Cov.: 33 AF XY: 0.0153 AC XY: 1137 AN XY: 74462

African (AFR) AF: 0.0551 AC: 2291 AN: 41564

American (AMR) AF: 0.00784 AC: 120 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68016

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00722 Hom.: 18

Bravo AF: 0.0187

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.64
DANN	Benign	0.82
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs61744155; hg19: chr9-131398633; COSMIC: COSV63985332; COSMIC: COSV63985332;