9-128635185-T-C

Variant names:

• chr9-128635185-T-C
• rs140034879
• NM_052844.4:c.888A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_052844.4(DYNC2I2):​c.888A>G​(p.Leu296Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,284 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L296L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0078 (4 hom., cov: 33)
  • Exomes 𝑓: 0.014 (182 hom.)
• Consequence: DYNC2I2 NM_052844.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.198

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-128635185-T-C is Benign according to our data. Variant chr9-128635185-T-C is described in ClinVar as [Benign]. Clinvar id is 474850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.198 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00783 (1192/152148) while in subpopulation NFE AF= 0.0134 (911/67974). AF 95% confidence interval is 0.0127. There are 4 homozygotes in gnomad4. There are 551 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I2	NM_052844.4	c.888A>G	p.Leu296Leu	synonymous_variant	Exon 6 of 9	ENST00000372715.7	NP_443076.2
DYNC2I2	XM_047424057.1	c.888A>G	p.Leu296Leu	synonymous_variant	Exon 7 of 10		XP_047280013.1
DYNC2I2	XM_011519179.3	c.814-10A>G		intron_variant	Intron 6 of 9		XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2I2	ENST00000372715.7	c.888A>G	p.Leu296Leu	synonymous_variant	Exon 6 of 9	1	NM_052844.4	ENSP00000361800.2

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1192 AN: 152030 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00552

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00547

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00745 AC: 1864 AN: 250062 Hom.: 7 AF XY: 0.00751 AC XY: 1018 AN XY: 135498

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.00475

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00436

Gnomad NFE exome AF: 0.0133

Gnomad OTH exome AF: 0.00704

GnomAD4 exome AF: 0.0140 AC: 20460 AN: 1461136 Hom.: 182 Cov.: 33 AF XY: 0.0136 AC XY: 9851 AN XY: 726904

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00499

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00413

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.00783 AC: 1192 AN: 152148 Hom.: 4 Cov.: 33 AF XY: 0.00741 AC XY: 551 AN XY: 74368

Gnomad4 AFR AF: 0.00299

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00547

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00878 Hom.: 4

Bravo AF: 0.00818

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYNC2I2: BP4, BS1, BS2 -

Short-rib thoracic dysplasia 11 with or without polydactyly Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.0
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs140034879; hg19: chr9-131397464;