11-103358299-T-C

Variant names:

• chr11-103358299-T-C
• rs2566913
• NM_001080463.2:c.12117T>C

Variant summary

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

The NM_001080463.2(DYNC2H1):​c.12117T>C​(p.Asp4039Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,589,806 control chromosomes in the GnomAD database, including 323,291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24777 hom., cov: 32)
  • Exomes 𝑓: 0.64 (298514 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.179
• Publications: 26 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), G2P, Orphanet, Ambry Genetics
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-103358299-T-C is Benign according to our data. Variant chr11-103358299-T-C is described in ClinVar as Benign. ClinVar VariationId is 302117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.179 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. 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.12117T>C	p.Asp4039Asp	synonymous	Exon 84 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.12096T>C	p.Asp4032Asp	synonymous	Exon 83 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.12117T>C	p.Asp4039Asp	synonymous	Exon 84 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.12096T>C	p.Asp4032Asp	synonymous	Exon 83 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2206-77644T>C		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83387 AN: 151878 Hom.: 24765 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.619 AC: 134827 AN: 217838 AF XY: 0.617

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.735

Gnomad ASJ exome AF: 0.613

Gnomad EAS exome AF: 0.508

Gnomad FIN exome AF: 0.663

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.640 AC: 920191 AN: 1437810 Hom.: 298514 Cov.: 37 AF XY: 0.638 AC XY: 454675 AN XY: 712966

African (AFR) AF: 0.276 AC: 9150 AN: 33116

American (AMR) AF: 0.724 AC: 30279 AN: 41798

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 15455 AN: 25598

East Asian (EAS) AF: 0.532 AC: 20787 AN: 39076

South Asian (SAS) AF: 0.530 AC: 43719 AN: 82444

European-Finnish (FIN) AF: 0.662 AC: 34477 AN: 52056

Middle Eastern (MID) AF: 0.565 AC: 3241 AN: 5740

European-Non Finnish (NFE) AF: 0.662 AC: 726899 AN: 1098444

Other (OTH) AF: 0.608 AC: 36184 AN: 59538

GnomAD4 genome AF: 0.549 AC: 83427 AN: 151996 Hom.: 24777 Cov.: 32 AF XY: 0.549 AC XY: 40787 AN XY: 74302

African (AFR) AF: 0.301 AC: 12472 AN: 41444

American (AMR) AF: 0.663 AC: 10129 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2107 AN: 3468

East Asian (EAS) AF: 0.512 AC: 2639 AN: 5150

South Asian (SAS) AF: 0.535 AC: 2579 AN: 4820

European-Finnish (FIN) AF: 0.643 AC: 6778 AN: 10548

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.658 AC: 44740 AN: 67970

Other (OTH) AF: 0.577 AC: 1220 AN: 2114

Alfa AF: 0.627 Hom.: 47795

Bravo AF: 0.544

Asia WGS AF: 0.533 AC: 1854 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.51
CADD	Benign	3.9
DANN	Benign	0.86
PhyloP100		0.18
PromoterAI		0.014	Neutral
Mutation Taster		=99/1	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: rs2566913; hg19: chr11-103229027; COSMIC: COSV62089585;