chr7-158926304-C-T

Variant names:

• chr7-158926304-C-T
• rs2286113
• NM_018051.5:c.2371+4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018051.5(DYNC2I1):​c.2371+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00928 in 1,608,350 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (213 hom., cov: 34)
  • Exomes 𝑓: 0.0071 (440 hom.)
• Consequence: DYNC2I1 NM_018051.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001356
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.43
• Publications: 5 publications found

Genes affected

DYNC2I1 (HGNC:21862): (dynein 2 intermediate chain 1) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD) and may facilitate the formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes including cell cycle progression, signal transduction, apoptosis, and gene regulation. The encoded protein contains four WD repeats and may play a role in the formation of cilia. Mutations in this gene have been associated with short-rib polydactyly and Jeune syndromes. [provided by RefSeq, Mar 2014]

DYNC2I1 Gene-Disease associations (from GenCC):

• short-rib thoracic dysplasia 8 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, G2P
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-158926304-C-T is Benign according to our data. Variant chr7-158926304-C-T is described in ClinVar as Benign. ClinVar VariationId is 474625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018051.5. 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
	DYNC2I1	NM_018051.5	MANE Select	c.2371+4C>T		splice_region intron	N/A	NP_060521.4
	DYNC2I1	NM_001350914.2		c.2233+4C>T		splice_region intron	N/A	NP_001337843.1
	DYNC2I1	NM_001350915.2		c.1798+4C>T		splice_region intron	N/A	NP_001337844.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2I1	ENST00000407559.8	TSL:1 MANE Select	c.2371+4C>T		splice_region intron	N/A	ENSP00000384290.3	Q8WVS4
	DYNC2I1	ENST00000444851.5	TSL:1	n.1529+4C>T		splice_region intron	N/A	ENSP00000392608.1	H7C022
	DYNC2I1	ENST00000860814.1		c.2446+4C>T		splice_region intron	N/A	ENSP00000530873.1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4519 AN: 152204 Hom.: 212 Cov.: 34

Gnomad AFR AF: 0.0844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0180 AC: 4277 AN: 237074 AF XY: 0.0166

Gnomad AFR exome AF: 0.0835

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000244

Gnomad OTH exome AF: 0.00707

GnomAD4 exome AF: 0.00714 AC: 10389 AN: 1456028 Hom.: 440 Cov.: 32 AF XY: 0.00714 AC XY: 5169 AN XY: 723798

African (AFR) AF: 0.0833 AC: 2781 AN: 33392

American (AMR) AF: 0.00368 AC: 161 AN: 43802

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 25986

East Asian (EAS) AF: 0.120 AC: 4735 AN: 39576

South Asian (SAS) AF: 0.0212 AC: 1801 AN: 85126

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53184

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5760

European-Non Finnish (NFE) AF: 0.000115 AC: 127 AN: 1108980

Other (OTH) AF: 0.0126 AC: 757 AN: 60222

GnomAD4 genome AF: 0.0297 AC: 4530 AN: 152322 Hom.: 213 Cov.: 34 AF XY: 0.0304 AC XY: 2264 AN XY: 74492

African (AFR) AF: 0.0842 AC: 3502 AN: 41580

American (AMR) AF: 0.0104 AC: 159 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.130 AC: 675 AN: 5178

South Asian (SAS) AF: 0.0263 AC: 127 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68028

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0115 Hom.: 39

Bravo AF: 0.0323

Asia WGS AF: 0.0600 AC: 208 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Short-rib thoracic dysplasia 8 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.055
DANN	Benign	0.47
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.012
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: rs2286113; hg19: chr7-158718995; COSMIC: COSV68105035;