2-171725598-GTTTTTT-GTTTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001378.3(DYNC1I2):​c.512-5_512-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 885,564 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00094 (1 hom., cov: 22)
  • Exomes 𝑓: 0.0038 (1 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 -1 ACMG points.

• BP6: Variant 2-171725598-GTT-G is Benign according to our data. Variant chr2-171725598-GTT-G is described in ClinVar as [Benign]. Clinvar id is 3056393.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3	c.512-5_512-4delTT		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.512-19_512-18delTT		intron_variant	Intron 7 of 17	1	NM_001378.3	ENSP00000380308.3

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 99 AN: 106072 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.000578

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.000866

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000198

Gnomad OTH AF: 0.00138

GnomAD2 exomes AF: 0.00964 AC: 392 AN: 40656 AF XY: 0.00996

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.0223

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.0436

Gnomad FIN exome AF: 0.00307

Gnomad NFE exome AF: 0.00797

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.00380 AC: 2962 AN: 779480 Hom.: 1 AF XY: 0.00383 AC XY: 1509 AN XY: 393814

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

African (AFR) AF: 0.00342 AC: 53 AN: 15514

American (AMR) AF: 0.00662 AC: 99 AN: 14944

Ashkenazi Jewish (ASJ) AF: 0.00263 AC: 39 AN: 14834

East Asian (EAS) AF: 0.0101 AC: 251 AN: 24828

South Asian (SAS) AF: 0.00408 AC: 159 AN: 38940

European-Finnish (FIN) AF: 0.00241 AC: 86 AN: 35714

Middle Eastern (MID) AF: 0.00482 AC: 11 AN: 2282

European-Non Finnish (NFE) AF: 0.00353 AC: 2114 AN: 598776

Other (OTH) AF: 0.00446 AC: 150 AN: 33648

⚠️ 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: 0.000943 AC: 100 AN: 106084 Hom.: 1 Cov.: 22 AF XY: 0.000786 AC XY: 40 AN XY: 50862

African (AFR) AF: 0.000577 AC: 16 AN: 27716

American (AMR) AF: 0.00102 AC: 11 AN: 10812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.0181 AC: 66 AN: 3638

South Asian (SAS) AF: 0.000869 AC: 3 AN: 3452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5106

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

European-Non Finnish (NFE) AF: 0.0000397 AC: 2 AN: 50374

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 19, 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		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746910264; hg19: chr2-172582108;