2-171725598-GTTTTTT-GTT

Variant names:

• chr2-171725598-GTTTT-G
• rs746910264
• NM_001378.3:c.512-7_512-4delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378.3(DYNC1I2):​c.512-7_512-4delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000964 in 788,540 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 16)
  • Exomes 𝑓: 0.000096 (0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I2	NM_001378.3	c.512-7_512-4delTTTT		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_512-16delTTTT		intron_variant	Intron 7 of 17	1	NM_001378.3	ENSP00000380308.3

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 0.0000964 AC: 76 AN: 788540 Hom.: 0 AF XY: 0.000105 AC XY: 42 AN XY: 398494

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

African (AFR) AF: 0.000191 AC: 3 AN: 15670

American (AMR) AF: 0.000262 AC: 4 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15026

East Asian (EAS) AF: 0.000197 AC: 5 AN: 25408

South Asian (SAS) AF: 0.000127 AC: 5 AN: 39506

European-Finnish (FIN) AF: 0.000110 AC: 4 AN: 36220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2308

European-Non Finnish (NFE) AF: 0.0000843 AC: 51 AN: 605038

Other (OTH) AF: 0.000117 AC: 4 AN: 34100

⚠️ 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 Cov.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97

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;