chr7-95813202-C-T

Variant names:

• chr7-95813202-C-T
• rs199740432
• ENST00000324972.10:c.230C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004411.5(DYNC1I1):​c.230C>T​(p.Pro77Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000119 in 1,611,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DYNC1I1 NM_004411.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.78

Genes affected

DYNC1I1 (HGNC:2963): (dynein cytoplasmic 1 intermediate chain 1) Enables spectrin binding activity. Involved in vesicle transport along microtubule. Located in several cellular components, including kinetochore; recycling endosome; and spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13351956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1I1	NM_001135556.2	c.224-45C>T		intron_variant	Intron 3 of 16	ENST00000447467.6	NP_001129028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1I1	ENST00000447467.6	c.224-45C>T		intron_variant	Intron 3 of 16	1	NM_001135556.2	ENSP00000392337.2

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 31 AN: 150782 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.0000985

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000325

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000164 AC: 41 AN: 250560 Hom.: 1 AF XY: 0.000177 AC XY: 24 AN XY: 135400

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000110 AC: 160 AN: 1460900 Hom.: 0 Cov.: 35 AF XY: 0.000125 AC XY: 91 AN XY: 726778

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.0000981

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000206 AC: 31 AN: 150782 Hom.: 0 Cov.: 30 AF XY: 0.000218 AC XY: 16 AN XY: 73522

Gnomad4 AFR AF: 0.000122

Gnomad4 AMR AF: 0.0000661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.0000985

Gnomad4 NFE AF: 0.000325

Gnomad4 OTH AF: 0.000484

Alfa AF: 0.000600 Hom.: 1

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230C>T (p.P77L) alteration is located in exon 4 (coding exon 3) of the DYNC1I1 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the proline (P) at amino acid position 77 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Mar 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 77 of the DYNC1I1 protein (p.Pro77Leu). This variant is present in population databases (rs199740432, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DYNC1I1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2198707). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	0.045
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.023	D;T
Polyphen		0.0	B;.
Vest4		0.17
MVP		0.83
MPC		0.56
ClinPred		0.085	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199740432; hg19: chr7-95442514; COSMIC: COSV61456028;