rs585692

Variant names:

• chr11-103176278-C-A
• rs585692
• NM_001080463.2:c.5718C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-103176278-C-A
• chr11-103176278-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001377.3(DYNC2H1):​c.5718C>A​(p.Thr1906Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 1,541,246 control chromosomes in the GnomAD database, including 661,347 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. T1906T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.94 (67723 hom., cov: 32)
  • Exomes 𝑓: 0.92 (593624 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.509
• Publications: 23 publications found

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, ClinGen
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 11-103176278-C-A is Benign according to our data. Variant chr11-103176278-C-A is described in ClinVar as Benign. ClinVar VariationId is 167011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.509 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377.3. 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
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.5718C>A	p.Thr1906Thr	synonymous	Exon 37 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.5718C>A	p.Thr1906Thr	synonymous	Exon 37 of 89	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.5718C>A	p.Thr1906Thr	synonymous	Exon 37 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.5718C>A	p.Thr1906Thr	synonymous	Exon 37 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+41859C>A		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.943 AC: 143403 AN: 152150 Hom.: 67652 Cov.: 32

Gnomad AFR AF: 0.980

Gnomad AMI AF: 0.971

Gnomad AMR AF: 0.942

Gnomad ASJ AF: 0.911

Gnomad EAS AF: 0.873

Gnomad SAS AF: 0.880

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.938

GnomAD2 exomes AF: 0.926 AC: 137631 AN: 148700 AF XY: 0.921

Gnomad AFR exome AF: 0.981

Gnomad AMR exome AF: 0.961

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.865

Gnomad FIN exome AF: 0.971

Gnomad NFE exome AF: 0.924

Gnomad OTH exome AF: 0.916

GnomAD4 exome AF: 0.924 AC: 1283516 AN: 1388978 Hom.: 593624 Cov.: 46 AF XY: 0.922 AC XY: 631398 AN XY: 684764

African (AFR) AF: 0.981 AC: 30344 AN: 30930

American (AMR) AF: 0.959 AC: 32701 AN: 34088

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 22837 AN: 25044

East Asian (EAS) AF: 0.855 AC: 29995 AN: 35086

South Asian (SAS) AF: 0.880 AC: 67125 AN: 76270

European-Finnish (FIN) AF: 0.969 AC: 47834 AN: 49386

Middle Eastern (MID) AF: 0.868 AC: 4916 AN: 5666

European-Non Finnish (NFE) AF: 0.925 AC: 994534 AN: 1074886

Other (OTH) AF: 0.924 AC: 53230 AN: 57622

GnomAD4 genome AF: 0.943 AC: 143533 AN: 152268 Hom.: 67723 Cov.: 32 AF XY: 0.942 AC XY: 70140 AN XY: 74432

African (AFR) AF: 0.980 AC: 40749 AN: 41572

American (AMR) AF: 0.942 AC: 14399 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.911 AC: 3163 AN: 3472

East Asian (EAS) AF: 0.873 AC: 4522 AN: 5178

South Asian (SAS) AF: 0.881 AC: 4241 AN: 4814

European-Finnish (FIN) AF: 0.976 AC: 10355 AN: 10614

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.926 AC: 62984 AN: 68018

Other (OTH) AF: 0.938 AC: 1979 AN: 2110

Alfa AF: 0.931 Hom.: 46023

Bravo AF: 0.943

Asia WGS AF: 0.853 AC: 2964 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	2	Jeune thoracic dystrophy (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		0.51
Mutation Taster		=96/4	polymorphism (auto)

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: rs585692; hg19: chr11-103047007; COSMIC: COSV108161705;