rs139730326

Positions:

• chr7-158887026-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001350917.2(DYNC2I1):​c.-426C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,613,532 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (16 hom., cov: 32)
  • Exomes 𝑓: 0.011 (97 hom.)
• Consequence: DYNC2I1 NM_001350917.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0930

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032497942).
• BP6: Variant 7-158887026-C-T is Benign according to our data. Variant chr7-158887026-C-T is described in ClinVar as [Benign]. Clinvar id is 474633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-158887026-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00971 (1479/152240) while in subpopulation NFE AF= 0.0146 (992/68022). AF 95% confidence interval is 0.0138. There are 16 homozygotes in gnomad4. There are 685 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2I1	NM_018051.5	c.941C>T	p.Ala314Val	missense_variant	7/25	ENST00000407559.8	NP_060521.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2I1	ENST00000407559.8	c.941C>T	p.Ala314Val	missense_variant	7/25	1	NM_018051.5	ENSP00000384290.3
DYNC2I1	ENST00000444851.5	n.272C>T		non_coding_transcript_exon_variant	3/20	1		ENSP00000392608.1
DYNC2I1	ENST00000467220.1	n.52C>T		non_coding_transcript_exon_variant	2/20	2

Frequencies

GnomAD3 genomes AF: 0.00972 AC: 1478 AN: 152122 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.00897

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00707

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00981 AC: 2444 AN: 249074 Hom.: 19 AF XY: 0.0106 AC XY: 1433 AN XY: 135122

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00739

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00664

Gnomad FIN exome AF: 0.00617

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0108 AC: 15750 AN: 1461292 Hom.: 97 Cov.: 30 AF XY: 0.0110 AC XY: 7974 AN XY: 726962

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00725

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00596

Gnomad4 FIN exome AF: 0.00620

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.00971 AC: 1479 AN: 152240 Hom.: 16 Cov.: 32 AF XY: 0.00920 AC XY: 685 AN XY: 74440

Gnomad4 AFR AF: 0.00222

Gnomad4 AMR AF: 0.00896

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00707

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0135 Hom.: 26

Bravo AF: 0.00946

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00217 AC: 8

ESP6500EA AF: 0.0128 AC: 105

ExAC AF: 0.0100 AC: 1212

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0160

EpiControl AF: 0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DYNC2I1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	10
DANN	Benign	0.92
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.0070
Sift	Benign	0.038	D
Sift4G	Benign	0.32	T
Polyphen		0.13	B
Vest4		0.18
MPC		0.19
ClinPred		0.0012	T
GERP RS		1.4
Varity_R		0.029
gMVP		0.051

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139730326; hg19: chr7-158679717;