Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001080463.2(DYNC2H1):c.10482A>G(p.Gln3494Gln) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,594,474 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 62 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 53 hom. )

Consequence

DYNC2H1
NM_001080463.2 splice_region, synonymous

Scores

Splicing: ADA: 0.0004273

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.20

Publications

3 publications found

Variant links:

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

DYNC2H1 links:

ENSG00000285878 (HGNC:):

ENSG00000285878 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 11-103256240-A-G is Benign according to our data. Variant chr11-103256240-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.2 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0146 (2227/152316) while in subpopulation AFR AF = 0.0506 (2102/41556). AF 95% confidence interval is 0.0488. There are 62 homozygotes in GnomAd4. There are 1036 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 62 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.10482A>G	p.Gln3494Gln	splice_region synonymous	Exon 69 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.10461A>G	p.Gln3487Gln	splice_region synonymous	Exon 68 of 89	NP_001368.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.10482A>G	p.Gln3494Gln	splice_region synonymous	Exon 69 of 90	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.10461A>G	p.Gln3487Gln	splice_region synonymous	Exon 68 of 89	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	TSL:1	c.2205+121821A>G		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2226

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00352

AC:

796

AN:

225988

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.0501

Gnomad AMR exome

AF:

0.00326

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000580

Gnomad OTH exome

AF:

0.000732

GnomAD4 exome

AF:

0.00139

AC:

1998

AN:

1442158

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

869

AN XY:

716230

show subpopulations

African (AFR)

AF:

0.0487

AC:

1585

AN:

32562

American (AMR)

AF:

0.00372

AC:

154

AN:

41442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25608

East Asian (EAS)

AF:

0.00

AC:

AN:

39096

South Asian (SAS)

AF:

0.000147

AC:

AN:

81546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52792

Middle Eastern (MID)

AF:

0.000880

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000525

AC:

AN:

1103760

Other (OTH)

AF:

0.00308

AC:

184

AN:

59670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0146

AC:

2227

AN:

152316

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1036

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0506

AC:

2102

AN:

41556

American (AMR)

AF:

0.00601

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68034

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

105

211

316

422

527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00577

Hom.:

Bravo

AF:

0.0167

Asia WGS

AF:

0.00347

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Asphyxiating thoracic dystrophy 3 (3)

Jeune thoracic dystrophy (1)

not provided (1)

not specified (1)

Short rib-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.9

(source)

DANN

Benign

0.71

PhyloP100

3.2

Mutation Taster

=18/82

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00043

dbscSNV1_RF

Benign

0.15

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs75143468

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over