2-171690205-G-A

Variant names:

• chr2-171690205-G-A
• rs1254884865
• NM_001378.3:c.50G>A

Variant summary

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

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. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• 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 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	c.50G>A	p.Arg17Gln	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.50G>A	p.Arg17Gln	missense_variant	Exon 2 of 18	1	NM_001378.3	ENSP00000380308.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000619 AC: 1 AN: 161662 AF XY: 0.0000117

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31672

American (AMR) AF: 0.00 AC: 0 AN: 35986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 36176

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5084

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1080566

Other (OTH) AF: 0.00 AC: 0 AN: 58132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.;.;.;.;.
PhyloP100		7.8
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
PromoterAI		-0.0015	Neutral
Varity_R		0.46
gMVP		0.19
Mutation Taster		=57/43	polymorphism

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

dbSNP: rs1254884865; hg19: chr2-172546715;