rs41271217

Variant names:

• chr7-158914326-A-G
• rs41271217
• NM_018051.5:c.1791+5A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018051.5(DYNC2I1):​c.1791+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,606,608 control chromosomes in the GnomAD database, including 342 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 0.012 (22 hom., cov: 33)
  • Exomes 𝑓: 0.019 (320 hom.)
• Consequence: DYNC2I1 NM_018051.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003873
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.769
• Publications: 2 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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=-0.92).
• BP6: Variant 7-158914326-A-G is Benign according to our data. Variant chr7-158914326-A-G is described in ClinVar as Benign. ClinVar VariationId is 474622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0123 (1874/152286) while in subpopulation NFE AF = 0.0213 (1449/68022). AF 95% confidence interval is 0.0204. There are 22 homozygotes in GnomAd4. There are 850 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2I1	NM_018051.5	c.1791+5A>G		splice_region_variant, intron_variant	Intron 14 of 24	ENST00000407559.8	NP_060521.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2I1	ENST00000407559.8	c.1791+5A>G		splice_region_variant, intron_variant	Intron 14 of 24	1	NM_018051.5	ENSP00000384290.3
DYNC2I1	ENST00000444851.5	n.1122+5A>G		splice_region_variant, intron_variant	Intron 10 of 19	1		ENSP00000392608.1
DYNC2I1	ENST00000467220.1	n.3590+5A>G		splice_region_variant, intron_variant	Intron 9 of 19	2

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1874 AN: 152168 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.0125 AC: 2973 AN: 237552 AF XY: 0.0128

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00648

Gnomad ASJ exome AF: 0.00716

Gnomad EAS exome AF: 0.0000575

Gnomad FIN exome AF: 0.00598

Gnomad NFE exome AF: 0.0211

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0186 AC: 27015 AN: 1454322 Hom.: 320 Cov.: 30 AF XY: 0.0182 AC XY: 13188 AN XY: 722874

African (AFR) AF: 0.00285 AC: 95 AN: 33390

American (AMR) AF: 0.00674 AC: 295 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.00652 AC: 169 AN: 25934

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39606

South Asian (SAS) AF: 0.00622 AC: 529 AN: 84994

European-Finnish (FIN) AF: 0.00737 AC: 391 AN: 53068

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5758

European-Non Finnish (NFE) AF: 0.0222 AC: 24591 AN: 1107740

Other (OTH) AF: 0.0153 AC: 921 AN: 60080

GnomAD4 genome AF: 0.0123 AC: 1874 AN: 152286 Hom.: 22 Cov.: 33 AF XY: 0.0114 AC XY: 850 AN XY: 74458

African (AFR) AF: 0.00358 AC: 149 AN: 41568

American (AMR) AF: 0.00673 AC: 103 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4824

European-Finnish (FIN) AF: 0.00500 AC: 53 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0213 AC: 1449 AN: 68022

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.0182 Hom.: 92

Bravo AF: 0.0120

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Short-rib thoracic dysplasia 8 with or without polydactyly Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.31
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0040
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: rs41271217; hg19: chr7-158707017;