2-171690205-G-A

Position:

• chr2-171690205-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001378.3(DYNC1I2):​c.50G>A​(p.Arg17Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,401,338 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: DYNC1I2 NM_001378.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DYNC1I2. . Gene score misZ 2.4516 (greater than the threshold 3.09). Trascript score misZ 3.3484 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with microcephaly and structural brain anomalies.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC1I2	NM_001378.3	c.50G>A	p.Arg17Gln	missense_variant	2/18	ENST00000397119.8	NP_001369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC1I2	ENST00000397119.8	c.50G>A	p.Arg17Gln	missense_variant	2/18	1	NM_001378.3	ENSP00000380308.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1401338 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 691594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.50G>A (p.R17Q) 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 50, causing the arginine (R) at amino acid position 17 to be replaced by a glutamine (Q). 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	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.071	T;.;T;.;T;.;.;T;.;T;.;.;T;T;T;.;.;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.6	.;M;M;M;.;M;M;.;M;M;.;M;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;D;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D;T;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;.;D;D;.;D;D;.;.;.;.;.;.;.;.;.
Vest4		0.34, 0.35, 0.32, 0.30, 0.26, 0.33, 0.31
MutPred		0.34		Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);Gain of ubiquitination at K15 (P = 0.0472);
MVP		0.89
MPC		1.5
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.46
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs1254884865; hg19: chr2-172546715;