Genetic Variant DYNC1I2:p.Leu53Phe (chr2-171692825-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378.3(DYNC1I2):c.157C>T(p.Leu53Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DYNC1I2
NM_001378.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.83

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3 link	c.157C>T	p.Leu53Phe	missense_variant	Exon 3 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.157C>T	p.Leu53Phe	missense_variant	Exon 3 of 18	1	NM_001378.3	ENSP00000380308.3		Q13409-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1457036

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724266

African (AFR)

AF:

0.00

AC:

AN:

33370

American (AMR)

AF:

0.00

AC:

AN:

44260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25970

East Asian (EAS)

AF:

0.00

AC:

AN:

39550

South Asian (SAS)

AF:

0.00

AC:

AN:

84934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109786

Other (OTH)

AF:

0.00

AC:

AN:

60240

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.157C>T (p.L53F) alteration is located in exon 3 (coding exon 2) of the DYNC1I2 gene. This alteration results from a C to T substitution at nucleotide position 157, causing the leucine (L) at amino acid position 53 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.084

T;.;T;.;T;.;.;T;.;T;.;.;T;T;T;.;.;.;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.6

.;M;M;M;.;M;M;.;M;M;.;M;.;.;.;.;.;.;.

PhyloP100

4.8

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.2

N;N;N;N;N;N;N;N;N;N;D;N;N;N;N;N;N;D;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.011

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.022

D;D;D;T;D;T;D;D;D;D;T;D;T;T;D;D;D;T;T

Polyphen

1.0, 1.0, 0.99

.;D;D;.;.;D;D;.;D;D;.;.;.;.;.;.;.;.;.

Vest4

0.54, 0.52, 0.48, 0.51, 0.51, 0.50, 0.52, 0.52

MutPred

0.20

Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);Gain of methylation at K55 (P = 0.1663);

MVP

0.93

MPC

1.5

ClinPred

0.96

GERP RS

5.7

Varity_R

0.33

gMVP

0.11

Mutation Taster

=59/41

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over