chr2-171715396-C-T

Variant names:

Variant summary

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

The NM_001378.3(DYNC1I2):c.464C>T(p.Thr155Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000051 in 1,569,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

DYNC1I2
NM_001378.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.88

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: 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.464C>T	p.Thr155Met	missense_variant	Exon 7 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.464C>T	p.Thr155Met	missense_variant	Exon 7 of 18	1	NM_001378.3	ENSP00000380308.3		Q13409-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

186152

AF XY:

0.0000101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000726

Gnomad ASJ exome

AF:

0.000111

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000353

AC:

AN:

1417060

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32484

American (AMR)

AF:

0.0000786

AC:

AN:

38158

Ashkenazi Jewish (ASJ)

AF:

0.0000394

AC:

AN:

25386

East Asian (EAS)

AF:

0.00

AC:

AN:

37760

South Asian (SAS)

AF:

0.00

AC:

AN:

80302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1087588

Other (OTH)

AF:

0.00

AC:

AN:

58816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.000131

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 26, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.464C>T (p.T155M) alteration is located in exon 7 (coding exon 6) of the DYNC1I2 gene. This alteration results from a C to T substitution at nucleotide position 464, causing the threonine (T) at amino acid position 155 to be replaced by a methionine (M). 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

Benign

0.15

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

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

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.43

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

MetaSVM

Uncertain

-0.087

MutationAssessor

Benign

1.2

.;.;L;.;.;.;.;.;.;L;L;.;.;.;.

PhyloP100

5.9

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.7

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.080

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

Sift4G

Uncertain

0.040

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

Polyphen

0.84, 0.97, 0.96

.;P;D;.;.;P;P;.;D;D;.;.;.;.;.

Vest4

0.35, 0.29, 0.34, 0.38, 0.39, 0.31, 0.28

MutPred

0.35

.;.;Loss of phosphorylation at T155 (P = 0.0287);.;.;.;.;.;.;Loss of phosphorylation at T155 (P = 0.0287);Loss of phosphorylation at T155 (P = 0.0287);.;.;.;.;

MVP

0.89

MPC

1.1

ClinPred

0.50

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.19

Mutation Taster

=33/67

disease causing

(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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chr2-171715396-C-T

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