chr7-158914326-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018051.5(DYNC2I1):c.1791+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,606,608 control chromosomes in the GnomAD database, including 342 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 Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 22 hom., cov: 33)

Exomes 𝑓: 0.019 ( 320 hom. )

Consequence

DYNC2I1
NM_018051.5 splice_region, intron

Scores

Splicing: ADA: 0.00003873

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.769

Publications

2 publications found

Variant links:

Genes affected

DYNC2I1 (HGNC:21862): (dynein 2 intermediate chain 1) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD) and may facilitate the formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes including cell cycle progression, signal transduction, apoptosis, and gene regulation. The encoded protein contains four WD repeats and may play a role in the formation of cilia. Mutations in this gene have been associated with short-rib polydactyly and Jeune syndromes. [provided by RefSeq, Mar 2014]

DYNC2I1 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 8 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Verma-Naumoff type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYNC2I1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 7-158914326-A-G is Benign according to our data. Variant chr7-158914326-A-G is described in ClinVar as Benign. ClinVar VariationId is 474622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0123 (1874/152286) while in subpopulation NFE AF = 0.0213 (1449/68022). AF 95% confidence interval is 0.0204. There are 22 homozygotes in GnomAd4. There are 850 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I1	NM_018051.5 link	c.1791+5A>G		splice_region_variant, intron_variant	Intron 14 of 24	ENST00000407559.8	NP_060521.4	Q8WVS4A0A140VK66

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DYNC2I1	ENST00000407559.8 link	c.1791+5A>G	splice_region_variant, intron_variant	Intron 14 of 24	1	NM_018051.5	ENSP00000384290.3	Q8WVS4
DYNC2I1	ENST00000444851.5 link	n.1122+5A>G	splice_region_variant, intron_variant	Intron 10 of 19	1		ENSP00000392608.1	H7C022
DYNC2I1	ENST00000467220.1 link	n.3590+5A>G	splice_region_variant, intron_variant	Intron 9 of 19	2

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1874

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00360

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.00680

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00500

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.0125

AC:

2973

AN:

237552

AF XY:

0.0128

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00648

Gnomad ASJ exome

AF:

0.00716

Gnomad EAS exome

AF:

0.0000575

Gnomad FIN exome

AF:

0.00598

Gnomad NFE exome

AF:

0.0211

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0186

AC:

27015

AN:

1454322

Hom.:

320

Cov.:

AF XY:

0.0182

AC XY:

13188

AN XY:

722874

show subpopulations

African (AFR)

AF:

0.00285

AC:

AN:

33390

American (AMR)

AF:

0.00674

AC:

295

AN:

43752

Ashkenazi Jewish (ASJ)

AF:

0.00652

AC:

169

AN:

25934

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39606

South Asian (SAS)

AF:

0.00622

AC:

529

AN:

84994

European-Finnish (FIN)

AF:

0.00737

AC:

391

AN:

53068

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0222

AC:

24591

AN:

1107740

Other (OTH)

AF:

0.0153

AC:

921

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

1122

2243

3365

4486

5608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.0123

AC:

1874

AN:

152286

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

850

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00358

AC:

149

AN:

41568

American (AMR)

AF:

0.00673

AC:

103

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3468

East Asian (EAS)

AF:

0.000580

AC:

AN:

5176

South Asian (SAS)

AF:

0.00539

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00500

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0213

AC:

1449

AN:

68022

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

192

289

385

481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0182

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Short-rib thoracic dysplasia 8 with or without polydactyly

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.16

(source)

DANN

Benign

0.31

PhyloP100

-0.77

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000039

dbscSNV1_RF

Benign

0.0040

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over