2-171725598-GTTTTTT-GTTTTTTTT

Variant names:

• chr2-171725598-G-GTT
• rs746910264
• NM_001378.3:c.512-5_512-4dupTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001378.3(DYNC1I2):​c.512-5_512-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 889,034 control chromosomes in the GnomAD database, including 64 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 22)
  • Exomes 𝑓: 0.012 (63 hom.)
• Consequence: DYNC1I2 NM_001378.3 splice_region, intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.112
• 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 2-171725598-G-GTT is Benign according to our data. Variant chr2-171725598-G-GTT is described in ClinVar as [Benign]. Clinvar id is 3056366.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3	c.512-5_512-4dupTT		splice_region_variant, 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.512-20_512-19insTT		intron_variant	Intron 7 of 17	1	NM_001378.3	ENSP00000380308.3

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 185 AN: 106052 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00120

Gnomad ASJ AF: 0.000376

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000289

Gnomad FIN AF: 0.000392

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000893

Gnomad OTH AF: 0.00138

GnomAD2 exomes AF: 0.0270 AC: 1098 AN: 40656 AF XY: 0.0291

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.0161

Gnomad FIN exome AF: 0.0219

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0125 AC: 9773 AN: 782970 Hom.: 63 Cov.: 15 AF XY: 0.0136 AC XY: 5362 AN XY: 395714

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

African (AFR) AF: 0.0117 AC: 181 AN: 15522

American (AMR) AF: 0.0105 AC: 159 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 292 AN: 14888

East Asian (EAS) AF: 0.00400 AC: 101 AN: 25222

South Asian (SAS) AF: 0.0291 AC: 1145 AN: 39298

European-Finnish (FIN) AF: 0.0157 AC: 563 AN: 35786

Middle Eastern (MID) AF: 0.0135 AC: 31 AN: 2290

European-Non Finnish (NFE) AF: 0.0114 AC: 6834 AN: 600976

Other (OTH) AF: 0.0138 AC: 467 AN: 33824

⚠️ 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 AF: 0.00174 AC: 185 AN: 106064 Hom.: 1 Cov.: 22 AF XY: 0.00191 AC XY: 97 AN XY: 50850

African (AFR) AF: 0.00437 AC: 121 AN: 27714

American (AMR) AF: 0.00120 AC: 13 AN: 10808

Ashkenazi Jewish (ASJ) AF: 0.000376 AC: 1 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3638

South Asian (SAS) AF: 0.000290 AC: 1 AN: 3452

European-Finnish (FIN) AF: 0.000392 AC: 2 AN: 5108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 186

European-Non Finnish (NFE) AF: 0.000894 AC: 45 AN: 50360

Other (OTH) AF: 0.00137 AC: 2 AN: 1462

Alfa AF: 0.00 Hom.: 46

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DYNC1I2-related disorder Benign:1

Nov 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746910264; hg19: chr2-172582108;