2-171725598-GTTTTTT-GTTTTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001378.3(DYNC1I2):​c.512-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 875,940 control chromosomes in the GnomAD database, including 3,314 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 0.21 (1993 hom., cov: 22)
  • Exomes 𝑓: 0.14 (1321 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-171725598-G-GT is Benign according to our data. Variant chr2-171725598-G-GT is described in ClinVar as [Benign]. Clinvar id is 3060840.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.207 AC: 21894 AN: 105840 Hom.: 1996 Cov.: 22

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.0583

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.233

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.199 AC: 8076 AN: 40656 AF XY: 0.199

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.139 AC: 107343 AN: 770090 Hom.: 1321 Cov.: 15 AF XY: 0.142 AC XY: 55121 AN XY: 389146

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

African (AFR) AF: 0.131 AC: 1987 AN: 15190

American (AMR) AF: 0.116 AC: 1723 AN: 14912

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 2819 AN: 14438

East Asian (EAS) AF: 0.142 AC: 3370 AN: 23726

South Asian (SAS) AF: 0.150 AC: 5896 AN: 39182

European-Finnish (FIN) AF: 0.183 AC: 6333 AN: 34578

Middle Eastern (MID) AF: 0.181 AC: 406 AN: 2248

European-Non Finnish (NFE) AF: 0.134 AC: 79690 AN: 592724

Other (OTH) AF: 0.155 AC: 5119 AN: 33092

⚠️ 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: 0.207 AC: 21893 AN: 105850 Hom.: 1993 Cov.: 22 AF XY: 0.203 AC XY: 10282 AN XY: 50754

African (AFR) AF: 0.203 AC: 5607 AN: 27624

American (AMR) AF: 0.159 AC: 1720 AN: 10788

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 721 AN: 2658

East Asian (EAS) AF: 0.0584 AC: 212 AN: 3630

South Asian (SAS) AF: 0.237 AC: 816 AN: 3442

European-Finnish (FIN) AF: 0.113 AC: 575 AN: 5100

Middle Eastern (MID) AF: 0.231 AC: 43 AN: 186

European-Non Finnish (NFE) AF: 0.235 AC: 11812 AN: 50286

Other (OTH) AF: 0.209 AC: 305 AN: 1458

Alfa AF: 0.0349 Hom.: 46

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DYNC1I2-related disorder Benign:1

Mar 11, 2024

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 (auto)

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;