2-171690183-G-A

Variant names:

• chr2-171690183-G-A
• NM_001378.3:c.28G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001378.3(DYNC1I2):​c.28G>A​(p.Glu10Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DYNC1I2 NM_001378.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.68
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3	c.28G>A	p.Glu10Lys	missense_variant	Exon 2 of 18	ENST00000397119.8	NP_001369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1I2	ENST00000397119.8	c.28G>A	p.Glu10Lys	missense_variant	Exon 2 of 18	1	NM_001378.3	ENSP00000380308.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.12e-7 AC: 1 AN: 1403690 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 692906

African (AFR) AF: 0.00 AC: 0 AN: 31784

American (AMR) AF: 0.00 AC: 0 AN: 36310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25208

East Asian (EAS) AF: 0.00 AC: 0 AN: 36394

South Asian (SAS) AF: 0.00 AC: 0 AN: 79006

European-Finnish (FIN) AF: 0.0000200 AC: 1 AN: 49918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082146

Other (OTH) AF: 0.00 AC: 0 AN: 58216

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.28G>A (p.E10K) alteration is located in exon 2 (coding exon 1) of the DYNC1I2 gene. This alteration results from a G to A substitution at nucleotide position 28, causing the glutamic acid (E) at amino acid position 10 to be replaced by a lysine (K). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;.;D;.;T;.;.;T;.;D;.;.;T;T;T;.;.;.;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.9	.;M;M;M;.;M;M;.;M;M;.;M;.;.;.;.;.;.;.
PhyloP100		9.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;T;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;.;D;D;.;D;D;.;.;.;.;.;.;.;.;.
Vest4		0.75, 0.74, 0.72, 0.74, 0.72, 0.77, 0.73
MutPred		0.30		Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);Loss of ubiquitination at K15 (P = 0.0256);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.022	Neutral
Varity_R		0.69
gMVP		0.38
Mutation Taster		=38/62	disease causing

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

Other links and lift over

hg19: chr2-172546693;