11-103109595-C-T

Variant names:

• chr11-103109595-C-T
• rs17301028
• NM_001080463.2:c.21C>T

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.21C>T​(p.Asp7Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 1,613,576 control chromosomes in the GnomAD database, including 7,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (436 hom., cov: 32)
  • Exomes 𝑓: 0.089 (6608 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.28
• Publications: 14 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=-0.44).
• BP6: Variant 11-103109595-C-T is Benign according to our data. Variant chr11-103109595-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 301995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0932 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.21C>T	p.Asp7Asp	synonymous	Exon 1 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.21C>T	p.Asp7Asp	synonymous	Exon 1 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.21C>T	p.Asp7Asp	synonymous	Exon 1 of 90	ENSP00000497174.1	Q8NCM8-2
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.21C>T	p.Asp7Asp	synonymous	Exon 1 of 89	ENSP00000364887.2	Q8NCM8-1
	DYNC2H1	ENST00000334267.11	TSL:1	c.21C>T	p.Asp7Asp	synonymous	Exon 1 of 20	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9955 AN: 152128 Hom.: 435 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0849

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0951

Gnomad OTH AF: 0.0753

GnomAD2 exomes AF: 0.0736 AC: 18308 AN: 248748 AF XY: 0.0776

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.0484

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.0960

Gnomad OTH exome AF: 0.0833

GnomAD4 exome AF: 0.0892 AC: 130393 AN: 1461330 Hom.: 6608 Cov.: 31 AF XY: 0.0897 AC XY: 65213 AN XY: 726904

African (AFR) AF: 0.0138 AC: 463 AN: 33480

American (AMR) AF: 0.0520 AC: 2326 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3571 AN: 26128

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39696

South Asian (SAS) AF: 0.0944 AC: 8139 AN: 86208

European-Finnish (FIN) AF: 0.0455 AC: 2429 AN: 53370

Middle Eastern (MID) AF: 0.127 AC: 733 AN: 5766

European-Non Finnish (NFE) AF: 0.0967 AC: 107514 AN: 1111612

Other (OTH) AF: 0.0863 AC: 5209 AN: 60366

GnomAD4 genome AF: 0.0654 AC: 9958 AN: 152246 Hom.: 436 Cov.: 32 AF XY: 0.0636 AC XY: 4735 AN XY: 74440

African (AFR) AF: 0.0191 AC: 792 AN: 41560

American (AMR) AF: 0.0709 AC: 1083 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3468

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0858 AC: 414 AN: 4826

European-Finnish (FIN) AF: 0.0459 AC: 487 AN: 10602

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0951 AC: 6469 AN: 68006

Other (OTH) AF: 0.0745 AC: 157 AN: 2106

Alfa AF: 0.0876 Hom.: 1102

Bravo AF: 0.0634

Asia WGS AF: 0.0280 AC: 100 AN: 3478

EpiCase AF: 0.0970

EpiControl AF: 0.102

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Jeune thoracic dystrophy (2)
-	-	1	Asphyxiating thoracic dystrophy 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		2.3
PromoterAI		0.0064	Neutral
Mutation Taster		=100/0	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: rs17301028; hg19: chr11-102980324; COSMIC: COSV107392413;