rs377094306

chr7-851458-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130965.3(SUN1):c.733C>G(p.Leu245Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,608,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SUN1 NM_001130965.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.29

Genes affected

SUN1 (HGNC:18587): (Sad1 and UNC84 domain containing 1) This gene is a member of the unc-84 homolog family and encodes a nuclear envelope protein with an Unc84 (SUN) domain. The protein is involved in nuclear anchorage and migration. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2019]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05062887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN1	NM_001130965.3	c.733C>G	p.Leu245Val	missense_variant	6/19	ENST00000401592.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN1	ENST00000401592.6	c.733C>G	p.Leu245Val	missense_variant	6/19	1	NM_001130965.3	P3

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000169 AC: 40 AN: 237230 Hom.: 0 AF XY: 0.000124 AC XY: 16 AN XY: 129034

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1456374 Hom.: 0 Cov.: 32 AF XY: 0.000123 AC XY: 89 AN XY: 723834

Gnomad4 AFR exome AF: 0.000629

Gnomad4 AMR exome AF: 0.000432

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.000349

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74356

Gnomad4 AFR AF: 0.000748

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.000382

ESP6500AA AF: 0.000638 AC: 2

ESP6500EA AF: 0.000279 AC: 2

ExAC AF: 0.000182 AC: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2021

The c.733C>G (p.L245V) alteration is located in exon 6 (coding exon 6) of the SUN1 gene. This alteration results from a C to G substitution at nucleotide position 733, causing the leucine (L) at amino acid position 245 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Emery-Dreifuss muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 245 of the SUN1 protein (p.Leu245Val). This variant is present in population databases (rs377094306, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SUN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 573750). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	15
Dann	Benign	0.86
DEOGEN2	Benign	0.023	T;.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.061
Sift	Benign	0.043	D;T;D
Sift4G	Benign	0.12	T;T;T
Vest4		0.30
MVP		0.15
MPC		0.40
ClinPred		0.039	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs377094306; hg19: chr7-891095; COSMIC: COSV100568880; COSMIC: COSV100568880;