2-171725598-GTTTTTT-GTTT

Variant names:

• chr2-171725598-GTTT-G
• rs746910264
• NM_001378.3:c.512-6_512-4delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001378.3(DYNC1I2):​c.512-6_512-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 892,732 control chromosomes in the GnomAD database, including 1 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 0.00017 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00074 (1 hom.)
• Consequence: DYNC1I2 NM_001378.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.970
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3	c.512-6_512-4delTTT		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_512-17delTTT		intron_variant	Intron 7 of 17	1	NM_001378.3	ENSP00000380308.3

Frequencies

GnomAD3 genomes AF: 0.000170 AC: 18 AN: 106062 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000926

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000274

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000980

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.000688

GnomAD4 exome AF: 0.000744 AC: 585 AN: 786658 Hom.: 1 AF XY: 0.000787 AC XY: 313 AN XY: 397462

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

African (AFR) AF: 0.000448 AC: 7 AN: 15614

American (AMR) AF: 0.000724 AC: 11 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.000667 AC: 10 AN: 14992

East Asian (EAS) AF: 0.00162 AC: 41 AN: 25280

South Asian (SAS) AF: 0.000813 AC: 32 AN: 39360

European-Finnish (FIN) AF: 0.00125 AC: 45 AN: 36090

Middle Eastern (MID) AF: 0.000435 AC: 1 AN: 2298

European-Non Finnish (NFE) AF: 0.000696 AC: 420 AN: 603794

Other (OTH) AF: 0.000529 AC: 18 AN: 34036

⚠️ 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: 0.000170 AC: 18 AN: 106074 Hom.: 0 Cov.: 22 AF XY: 0.000157 AC XY: 8 AN XY: 50858

African (AFR) AF: 0.000144 AC: 4 AN: 27714

American (AMR) AF: 0.0000925 AC: 1 AN: 10810

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

East Asian (EAS) AF: 0.000275 AC: 1 AN: 3638

South Asian (SAS) AF: 0.00 AC: 0 AN: 3452

European-Finnish (FIN) AF: 0.000980 AC: 5 AN: 5104

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

European-Non Finnish (NFE) AF: 0.000119 AC: 6 AN: 50370

Other (OTH) AF: 0.000684 AC: 1 AN: 1462

Alfa AF: 0.00 Hom.: 46

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
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;