rs3821091

Variant names:

• chr2-171725602-T-G
• rs3821091
• NM_001378.3:c.512-16T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001378.3(DYNC1I2):​c.512-16T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 16)
  • Exomes 𝑓: 0.0082 (6 hom.)
• Consequence: DYNC1I2 NM_001378.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.429
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-171725602-T-G is Benign according to our data. Variant chr2-171725602-T-G is described in ClinVar as Benign. ClinVar VariationId is 402814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3	c.512-16T>G		intron_variant	Intron 7 of 17	ENST00000397119.8	NP_001369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1I2	ENST00000397119.8	c.512-16T>G		intron_variant	Intron 7 of 17	1	NM_001378.3	ENSP00000380308.3

Frequencies

GnomAD3 genomes AF: 0.000573 AC: 46 AN: 80294 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000568

Gnomad ASJ AF: 0.00498

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.000303

Gnomad FIN AF: 0.000169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000369

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0248 AC: 1478 AN: 59630 AF XY: 0.0254

Gnomad AFR exome AF: 0.0492

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0232

Gnomad EAS exome AF: 0.0276

Gnomad FIN exome AF: 0.00849

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0255

GnomAD4 exome AF: 0.00823 AC: 7297 AN: 886700 Hom.: 6 Cov.: 18 AF XY: 0.00848 AC XY: 3741 AN XY: 441232

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

African (AFR) AF: 0.0109 AC: 188 AN: 17318

American (AMR) AF: 0.00871 AC: 127 AN: 14582

Ashkenazi Jewish (ASJ) AF: 0.00954 AC: 145 AN: 15206

East Asian (EAS) AF: 0.00497 AC: 138 AN: 27750

South Asian (SAS) AF: 0.00639 AC: 287 AN: 44892

European-Finnish (FIN) AF: 0.00393 AC: 151 AN: 38448

Middle Eastern (MID) AF: 0.00743 AC: 21 AN: 2826

European-Non Finnish (NFE) AF: 0.00866 AC: 5959 AN: 687712

Other (OTH) AF: 0.00740 AC: 281 AN: 37966

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000585 AC: 47 AN: 80374 Hom.: 0 Cov.: 16 AF XY: 0.000501 AC XY: 20 AN XY: 39894

African (AFR) AF: 0.000693 AC: 14 AN: 20192

American (AMR) AF: 0.000568 AC: 5 AN: 8804

Ashkenazi Jewish (ASJ) AF: 0.00498 AC: 9 AN: 1808

East Asian (EAS) AF: 0.00117 AC: 4 AN: 3410

South Asian (SAS) AF: 0.000304 AC: 1 AN: 3288

European-Finnish (FIN) AF: 0.000169 AC: 1 AN: 5930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 158

European-Non Finnish (NFE) AF: 0.000369 AC: 13 AN: 35190

Other (OTH) AF: 0.00 AC: 0 AN: 1104

Alfa AF: 0.0144 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.29
DANN	Benign	0.38
PhyloP100		-0.43
Mutation Taster		=100/0	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: rs3821091; hg19: chr2-172582112;