NM_001378.3:c.512-16T>G

Variant names:

• chr2-171725602-T-G
• rs3821091
• NM_001378.3:c.512-16T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001378.3(DYNC1I2):​c.512-16T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 16)
  • Exomes 𝑓: 0.0082 (6 hom.)
• Consequence: DYNC1I2 NM_001378.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.429
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-171725602-T-G is Benign according to our data. Variant chr2-171725602-T-G is described in ClinVar as Benign. ClinVar VariationId is 402814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1I2	NM_001378.3	MANE Select	c.512-16T>G		intron	N/A	NP_001369.1	Q13409-1
	DYNC1I2	NM_001271785.2		c.512-16T>G		intron	N/A	NP_001258714.1	Q13409-1
	DYNC1I2	NM_001320882.2		c.494-16T>G		intron	N/A	NP_001307811.1	Q13409-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1I2	ENST00000397119.8	TSL:1 MANE Select	c.512-16T>G		intron	N/A	ENSP00000380308.3	Q13409-1
	DYNC1I2	ENST00000340296.8	TSL:1	c.434-16T>G		intron	N/A	ENSP00000339430.4	Q13409-3
	DYNC1I2	ENST00000409197.5	TSL:1	c.434-16T>G		intron	N/A	ENSP00000386397.1	Q13409-3

Frequencies

GnomAD3 genomes AF: 0.000573 AC: 46 AN: 80294 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000568

Gnomad ASJ AF: 0.00498

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.000303

Gnomad FIN AF: 0.000169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000369

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0248 AC: 1478 AN: 59630 AF XY: 0.0254

Gnomad AFR exome AF: 0.0492

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0232

Gnomad EAS exome AF: 0.0276

Gnomad FIN exome AF: 0.00849

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0255

GnomAD4 exome AF: 0.00823 AC: 7297 AN: 886700 Hom.: 6 Cov.: 18 AF XY: 0.00848 AC XY: 3741 AN XY: 441232

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

African (AFR) AF: 0.0109 AC: 188 AN: 17318

American (AMR) AF: 0.00871 AC: 127 AN: 14582

Ashkenazi Jewish (ASJ) AF: 0.00954 AC: 145 AN: 15206

East Asian (EAS) AF: 0.00497 AC: 138 AN: 27750

South Asian (SAS) AF: 0.00639 AC: 287 AN: 44892

European-Finnish (FIN) AF: 0.00393 AC: 151 AN: 38448

Middle Eastern (MID) AF: 0.00743 AC: 21 AN: 2826

European-Non Finnish (NFE) AF: 0.00866 AC: 5959 AN: 687712

Other (OTH) AF: 0.00740 AC: 281 AN: 37966

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000585 AC: 47 AN: 80374 Hom.: 0 Cov.: 16 AF XY: 0.000501 AC XY: 20 AN XY: 39894

African (AFR) AF: 0.000693 AC: 14 AN: 20192

American (AMR) AF: 0.000568 AC: 5 AN: 8804

Ashkenazi Jewish (ASJ) AF: 0.00498 AC: 9 AN: 1808

East Asian (EAS) AF: 0.00117 AC: 4 AN: 3410

South Asian (SAS) AF: 0.000304 AC: 1 AN: 3288

European-Finnish (FIN) AF: 0.000169 AC: 1 AN: 5930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 158

European-Non Finnish (NFE) AF: 0.000369 AC: 13 AN: 35190

Other (OTH) AF: 0.00 AC: 0 AN: 1104

Alfa AF: 0.0144 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.29
DANN	Benign	0.38
PhyloP100		-0.43
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: rs3821091; hg19: chr2-172582112;