rs586592

Variant names:

• chr11-103187397-C-T
• rs586592
• NM_001080463.2:c.6951C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-103187397-C-T
• chr11-103187397-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.6951C>T​(p.His2317His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,612,840 control chromosomes in the GnomAD database, including 310,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31003 hom., cov: 31)
  • Exomes 𝑓: 0.62 (279605 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.71
• Publications: 22 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=-0.46).
• BP6: Variant 11-103187397-C-T is Benign according to our data. Variant chr11-103187397-C-T is described in ClinVar as Benign. ClinVar VariationId is 93529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.694 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.6951C>T	p.His2317His	synonymous	Exon 43 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.6951C>T	p.His2317His	synonymous	Exon 43 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.6951C>T	p.His2317His	synonymous	Exon 43 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.6951C>T	p.His2317His	synonymous	Exon 43 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+52978C>T		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96667 AN: 151742 Hom.: 30974 Cov.: 31

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.705

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.627

GnomAD2 exomes AF: 0.637 AC: 158480 AN: 248682 AF XY: 0.630

Gnomad AFR exome AF: 0.663

Gnomad AMR exome AF: 0.766

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.542

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.629

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.617 AC: 901343 AN: 1460980 Hom.: 279605 Cov.: 63 AF XY: 0.614 AC XY: 446597 AN XY: 726778

African (AFR) AF: 0.672 AC: 22459 AN: 33444

American (AMR) AF: 0.756 AC: 33801 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 17547 AN: 26096

East Asian (EAS) AF: 0.503 AC: 19964 AN: 39656

South Asian (SAS) AF: 0.557 AC: 48071 AN: 86244

European-Finnish (FIN) AF: 0.635 AC: 33911 AN: 53398

Middle Eastern (MID) AF: 0.651 AC: 3754 AN: 5766

European-Non Finnish (NFE) AF: 0.616 AC: 684390 AN: 1111360

Other (OTH) AF: 0.621 AC: 37446 AN: 60330

GnomAD4 genome AF: 0.637 AC: 96753 AN: 151860 Hom.: 31003 Cov.: 31 AF XY: 0.636 AC XY: 47167 AN XY: 74214

African (AFR) AF: 0.666 AC: 27556 AN: 41404

American (AMR) AF: 0.705 AC: 10734 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2348 AN: 3472

East Asian (EAS) AF: 0.551 AC: 2846 AN: 5164

South Asian (SAS) AF: 0.549 AC: 2650 AN: 4826

European-Finnish (FIN) AF: 0.629 AC: 6643 AN: 10554

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42040 AN: 67910

Other (OTH) AF: 0.629 AC: 1325 AN: 2108

Alfa AF: 0.633 Hom.: 18599

Bravo AF: 0.647

Asia WGS AF: 0.559 AC: 1944 AN: 3476

EpiCase AF: 0.631

EpiControl AF: 0.635

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	1	Jeune thoracic dystrophy (1)
-	-	1	not provided (1)
-	-	1	Short rib-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.4
DANN	Benign	0.40
PhyloP100		2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs586592; hg19: chr11-103058126; COSMIC: COSV62088517;