rs143753088

Variant names:

• chr7-158913079-G-A
• rs143753088
• NM_018051.5:c.1685G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018051.5(DYNC2I1):​c.1685G>A​(p.Ser562Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000886 in 1,612,986 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (4 hom.)
• Consequence: DYNC2I1 NM_018051.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.55
• Publications: 6 publications found

Genes affected

DYNC2I1 (HGNC:21862): (dynein 2 intermediate chain 1) 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) and may facilitate the 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. The encoded protein contains four WD repeats and may play a role in the formation of cilia. Mutations in this gene have been associated with short-rib polydactyly and Jeune syndromes. [provided by RefSeq, Mar 2014]

DYNC2I1 Gene-Disease associations (from GenCC):

• short-rib thoracic dysplasia 8 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048060417).
• BP6: Variant 7-158913079-G-A is Benign according to our data. Variant chr7-158913079-G-A is described in ClinVar as Benign. ClinVar VariationId is 474621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00493 (751/152340) while in subpopulation AFR AF = 0.0175 (726/41580). AF 95% confidence interval is 0.0164. There are 3 homozygotes in GnomAd4. There are 328 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018051.5. 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
	DYNC2I1	NM_018051.5	MANE Select	c.1685G>A	p.Ser562Asn	missense	Exon 13 of 25	NP_060521.4
	DYNC2I1	NM_001350914.2		c.1547G>A	p.Ser516Asn	missense	Exon 13 of 25	NP_001337843.1
	DYNC2I1	NM_001350915.2		c.1112G>A	p.Ser371Asn	missense	Exon 12 of 24	NP_001337844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I1	ENST00000407559.8	TSL:1 MANE Select	c.1685G>A	p.Ser562Asn	missense	Exon 13 of 25	ENSP00000384290.3	Q8WVS4
	DYNC2I1	ENST00000444851.5	TSL:1	n.1016G>A		non_coding_transcript_exon	Exon 9 of 20	ENSP00000392608.1	H7C022
	DYNC2I1	ENST00000860814.1		c.1760G>A	p.Ser587Asn	missense	Exon 14 of 26	ENSP00000530873.1

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152222 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00117 AC: 291 AN: 248198 AF XY: 0.000788

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000464 AC: 678 AN: 1460646 Hom.: 4 Cov.: 29 AF XY: 0.000370 AC XY: 269 AN XY: 726598

African (AFR) AF: 0.0174 AC: 581 AN: 33446

American (AMR) AF: 0.000582 AC: 26 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111238

Other (OTH) AF: 0.000995 AC: 60 AN: 60326

GnomAD4 genome AF: 0.00493 AC: 751 AN: 152340 Hom.: 3 Cov.: 33 AF XY: 0.00440 AC XY: 328 AN XY: 74492

African (AFR) AF: 0.0175 AC: 726 AN: 41580

American (AMR) AF: 0.00118 AC: 18 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00192 Hom.: 2

Bravo AF: 0.00557

ESP6500AA AF: 0.0163 AC: 62

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.00145 AC: 175

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Short-rib thoracic dysplasia 8 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.24
Sift	Benign	0.20	T
Sift4G	Benign	0.67	T
Polyphen		0.70	P
Vest4		0.26
MVP		0.78
MPC		0.21
ClinPred		0.011	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.085
Mutation Taster		=92/8	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: rs143753088; hg19: chr7-158705770;