Genetic Variant SFT2D2:p.Lys6Asn (chr1-168226097-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_199344.3(SFT2D2):c.18G>C(p.Lys6Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,534,824 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 1 hom. )

Consequence

SFT2D2
NM_199344.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.560

Variant links:

Genes affected

SFT2D2 (HGNC:25140): (SFT2 domain containing 2) Predicted to be involved in protein transport and vesicle-mediated transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

SFT2D2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.018986732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFT2D2	NM_199344.3 link	c.18G>C	p.Lys6Asn	missense_variant	Exon 1 of 8	ENST00000271375.7	NP_955376.1	O95562

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SFT2D2	ENST00000271375.7 link	c.18G>C	p.Lys6Asn	missense_variant	Exon 1 of 8	1	NM_199344.3	ENSP00000271375.3	O95562
SFT2D2	ENST00000367829.5 link	c.18G>C	p.Lys6Asn	missense_variant	Exon 1 of 6	5		ENSP00000356803.1	Q5TIH2
SFT2D2	ENST00000630869.1 link	c.18G>C	p.Lys6Asn	missense_variant	Exon 1 of 7	4		ENSP00000486492.1	Q5TIH2
SFT2D2	ENST00000471981.1 link	n.160G>C		non_coding_transcript_exon_variant	Exon 1 of 7	5

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000454

AC:

AN:

141008

Hom.:

AF XY:

0.000470

AC XY:

AN XY:

74502

show subpopulations

Gnomad AFR exome

AF:

0.000142

Gnomad AMR exome

AF:

0.000728

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000630

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000603

Gnomad OTH exome

AF:

0.000255

GnomAD4 exome

AF:

0.000351

AC:

485

AN:

1382546

Hom.:

Cov.:

AF XY:

0.000412

AC XY:

281

AN XY:

681648

show subpopulations

Gnomad4 AFR exome

AF:

0.0000663

Gnomad4 AMR exome

AF:

0.000620

Gnomad4 ASJ exome

AF:

0.000161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00104

Gnomad4 FIN exome

AF:

0.0000407

Gnomad4 NFE exome

AF:

0.000328

Gnomad4 OTH exome

AF:

0.000297

GnomAD4 genome

AF:

0.000532

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000399

Hom.:

Bravo

AF:

0.000419

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000460

AC:

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.18G>C (p.K6N) alteration is located in exon 1 (coding exon 1) of the SFT2D2 gene. This alteration results from a G to C substitution at nucleotide position 18, causing the lysine (K) at amino acid position 6 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.030

T;T;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.77

.;T;T

M_CAP

Benign

0.078

MetaRNN

Benign

0.019

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;.;L

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.9

N;.;N

REVEL

Benign

0.050

Sift

Uncertain

0.018

D;.;T

Sift4G

Uncertain

0.019

D;D;T

Polyphen

0.035

.;.;B

Vest4

0.16

MutPred

0.27

Loss of methylation at K6 (P = 0.0117);Loss of methylation at K6 (P = 0.0117);Loss of methylation at K6 (P = 0.0117);

MVP

0.048

MPC

0.35

ClinPred

0.021

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over