chr3-57913179-A-G

Variant names:

• chr3-57913179-A-G
• rs150439110
• NM_001377540.1:c.2042A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001377540.1(SLMAP):​c.2042A>G​(p.Lys681Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,576,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: SLMAP NM_001377540.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.22
• Publications: 5 publications found

Genes affected

SLMAP (HGNC:16643): (sarcolemma associated protein) This gene encodes a component of a conserved striatin-interacting phosphatase and kinase complex. Striatin family complexes participate in a variety of cellular processes including signaling, cell cycle control, cell migration, Golgi assembly, and apoptosis. The protein encoded by this gene is a coiled-coil, tail-anchored membrane protein with a single C-terminal transmembrane domain that is posttranslationally inserted into membranes. Mutations in this gene are associated with Brugada syndrome, a cardiac channelopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

SLMAP Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Orphanet, ClinGen

LOC105377103 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046085775).
• BP6: Variant 3-57913179-A-G is Benign according to our data. Variant chr3-57913179-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 411199.
• BS2: High AC in GnomAd4 at 39 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377540.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLMAP	NM_001377540.1	MANE Select	c.2042A>G	p.Lys681Arg	missense	Exon 21 of 25	NP_001364469.1
	SLMAP	NM_001377538.1		c.2063A>G	p.Lys688Arg	missense	Exon 21 of 24	NP_001364467.1
	SLMAP	NM_001377539.1		c.2042A>G	p.Lys681Arg	missense	Exon 21 of 24	NP_001364468.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLMAP	ENST00000671191.1	MANE Select	c.2042A>G	p.Lys681Arg	missense	Exon 21 of 25	ENSP00000499458.1
	SLMAP	ENST00000417128.7	TSL:1	c.1928A>G	p.Lys643Arg	missense	Exon 19 of 23	ENSP00000412829.3
	SLMAP	ENST00000449503.6	TSL:1	c.1877A>G	p.Lys626Arg	missense	Exon 17 of 20	ENSP00000412945.2

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000228 AC: 57 AN: 249910 AF XY: 0.000244

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000398 AC: 566 AN: 1423722 Hom.: 0 Cov.: 26 AF XY: 0.000371 AC XY: 263 AN XY: 709806

African (AFR) AF: 0.0000609 AC: 2 AN: 32852

American (AMR) AF: 0.000113 AC: 5 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25592

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 83208

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.000496 AC: 536 AN: 1081316

Other (OTH) AF: 0.000340 AC: 20 AN: 58832

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74496

African (AFR) AF: 0.000120 AC: 5 AN: 41586

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000420 Hom.: 0

Bravo AF: 0.000306

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 20

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.037
Sift	Uncertain	0.015	D
Sift4G	Benign	0.10	T
Polyphen		0.20	B
Vest4		0.084
MVP		0.70
MPC		0.16
ClinPred		0.063	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.053
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs150439110; hg19: chr3-57898906;