2-171725598-GTTTTTT-GTTTTT

Variant names:

• chr2-171725598-GT-G
• rs746910264
• NM_001378.3:c.512-4delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001378.3(DYNC1I2):​c.512-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 879,754 control chromosomes in the GnomAD database, including 88 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (41 hom., cov: 22)
  • Exomes 𝑓: 0.056 (47 hom.)
• Consequence: DYNC1I2 NM_001378.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0818 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 3111 AN: 106018 Hom.: 41 Cov.: 22

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0221

Gnomad AMR AF: 0.0863

Gnomad ASJ AF: 0.00527

Gnomad EAS AF: 0.00906

Gnomad SAS AF: 0.0185

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.0149

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.120 AC: 4891 AN: 40656 AF XY: 0.118

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.0794

Gnomad EAS exome AF: 0.156

Gnomad FIN exome AF: 0.0923

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.0563 AC: 43568 AN: 773724 Hom.: 47 Cov.: 15 AF XY: 0.0564 AC XY: 22061 AN XY: 390810

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

African (AFR) AF: 0.0388 AC: 597 AN: 15378

American (AMR) AF: 0.102 AC: 1507 AN: 14840

Ashkenazi Jewish (ASJ) AF: 0.0379 AC: 554 AN: 14610

East Asian (EAS) AF: 0.0782 AC: 1864 AN: 23836

South Asian (SAS) AF: 0.0452 AC: 1754 AN: 38844

European-Finnish (FIN) AF: 0.0660 AC: 2308 AN: 34984

Middle Eastern (MID) AF: 0.0563 AC: 127 AN: 2256

European-Non Finnish (NFE) AF: 0.0552 AC: 32887 AN: 595688

Other (OTH) AF: 0.0592 AC: 1970 AN: 33288

⚠️ 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: 0.0294 AC: 3118 AN: 106030 Hom.: 41 Cov.: 22 AF XY: 0.0296 AC XY: 1504 AN XY: 50830

African (AFR) AF: 0.0109 AC: 303 AN: 27702

American (AMR) AF: 0.0864 AC: 934 AN: 10804

Ashkenazi Jewish (ASJ) AF: 0.00527 AC: 14 AN: 2658

East Asian (EAS) AF: 0.00908 AC: 33 AN: 3634

South Asian (SAS) AF: 0.0188 AC: 65 AN: 3452

European-Finnish (FIN) AF: 0.0284 AC: 145 AN: 5108

Middle Eastern (MID) AF: 0.0161 AC: 3 AN: 186

European-Non Finnish (NFE) AF: 0.0309 AC: 1555 AN: 50348

Other (OTH) AF: 0.0349 AC: 51 AN: 1460

Alfa AF: 0.00433 Hom.: 46

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11
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: rs746910264; hg19: chr2-172582108;