NM_001378.3:c.49C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_001378.3(DYNC1I2):c.49C>T(p.Arg17*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000452 in 1,549,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

DYNC1I2
NM_001378.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.93

Publications

1 publications found

Variant links:

Genes affected

DYNC1I2 (HGNC:2964): (dynein cytoplasmic 1 intermediate chain 2) This gene encodes a member of the dynein intermediate chain family. The encoded protein is a non-catalytic component of the cytoplasmic dynein 1 complex, which acts as a retrograde microtubule motor to transport organelles and vesicles. A pseudogene of this gene is located on chromosome 10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

DYNC1I2 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly and structural brain anomalies
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

DYNC1I2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.974 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-171690204-C-T is Pathogenic according to our data. Variant chr2-171690204-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2817809.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3 link	c.49C>T	p.Arg17*	stop_gained	Exon 2 of 18	ENST00000397119.8	NP_001369.1	Q13409-1A0A140VKE9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1I2	ENST00000397119.8 link	c.49C>T	p.Arg17*	stop_gained	Exon 2 of 18	1	NM_001378.3	ENSP00000380308.3		Q13409-1

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000990

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000429

AC:

AN:

1399244

Hom.:

Cov.:

AF XY:

0.00000434

AC XY:

AN XY:

690542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25082

East Asian (EAS)

AF:

0.00

AC:

AN:

36100

South Asian (SAS)

AF:

0.00

AC:

AN:

78452

European-Finnish (FIN)

AF:

0.0000805

AC:

AN:

49692

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5032

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1079358

Other (OTH)

AF:

0.00

AC:

AN:

58028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150444

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40790

American (AMR)

AF:

0.00

AC:

AN:

15122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4758

European-Finnish (FIN)

AF:

0.0000990

AC:

AN:

10102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67752

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jan 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg17*) in the DYNC1I2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYNC1I2 are known to be pathogenic (PMID: 31079899). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DYNC1I2-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

PhyloP100

5.9

Vest4

0.41, 0.41, 0.43, 0.43, 0.42, 0.41

GERP RS

4.8

PromoterAI

0.020

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Mutation Taster

=4/196

disease causing (fs/PTC)

(source)

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

Publications

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NM_001378.3:c.49C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over