2-171690263-A-T

Variant names:

• chr2-171690263-A-T
• rs757274921
• NM_001378.3:c.108A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378.3(DYNC1I2):​c.108A>T​(p.Glu36Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000747 in 1,539,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: DYNC1I2 NM_001378.3 missense, splice_region
• Scores: Splicing: ADA: 0.002489
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17569923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3	c.108A>T	p.Glu36Asp	missense_variant, splice_region_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.108A>T	p.Glu36Asp	missense_variant, splice_region_variant	Exon 2 of 18	1	NM_001378.3	ENSP00000380308.3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000274 AC: 4 AN: 146136 AF XY: 0.0000520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000446

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000793 AC: 110 AN: 1386808 Hom.: 0 Cov.: 28 AF XY: 0.0000863 AC XY: 59 AN XY: 683750

African (AFR) AF: 0.00 AC: 0 AN: 30716

American (AMR) AF: 0.0000299 AC: 1 AN: 33460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24862

East Asian (EAS) AF: 0.00 AC: 0 AN: 35612

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.0000978 AC: 105 AN: 1073806

Other (OTH) AF: 0.0000522 AC: 3 AN: 57466

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000294 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 36 of the DYNC1I2 protein (p.Glu36Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DYNC1I2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0082	T;.;T;.;T;.;.;T;.;T;.;.;T;T;T;.;.;.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	.;L;L;L;.;L;L;.;L;L;.;L;.;.;.;.;.;.;.
PhyloP100		2.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.75	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.56	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0040, 0.0010	.;B;B;.;.;B;B;.;B;B;.;.;.;.;.;.;.;.;.
Vest4		0.52, 0.34, 0.40, 0.37, 0.38, 0.33, 0.35
MutPred		0.12		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.80
MPC		0.46
ClinPred		0.19	T
GERP RS		3.6
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.4
Varity_R		0.075
gMVP		0.066
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.14
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: rs757274921; hg19: chr2-172546773;