2-54664623-G-A

Variant names:

• chr2-54664623-G-A
• rs149619575
• NM_003128.3:c.6591G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003128.3(SPTBN1):​c.6591G>A​(p.Ser2197Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,614,166 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (46 hom.)
• Consequence: SPTBN1 NM_003128.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.39
• Publications: 3 publications found

Genes affected

SPTBN1 (HGNC:11275): (spectrin beta, non-erythrocytic 1) Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein contains an N-terminal actin-binding domain, and 17 spectrin repeats which are involved in dimer formation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SPTBN1-AS2 (HGNC:40563): (SPTBN1 antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-54664623-G-A is Benign according to our data. Variant chr2-54664623-G-A is described in ClinVar as [Benign]. Clinvar id is 718424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00246 (374/152274) while in subpopulation EAS AF = 0.0139 (72/5178). AF 95% confidence interval is 0.0122. There are 3 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 374 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN1	NM_003128.3	c.6591G>A	p.Ser2197Ser	synonymous_variant	Exon 33 of 36	ENST00000356805.9	NP_003119.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN1	ENST00000356805.9	c.6591G>A	p.Ser2197Ser	synonymous_variant	Exon 33 of 36	1	NM_003128.3	ENSP00000349259.4
SPTBN1	ENST00000467371.1	n.1723G>A		non_coding_transcript_exon_variant	Exon 1 of 4	2
SPTBN1-AS2	ENST00000626206.1	n.441C>T		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 374 AN: 152156 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00669 AC: 1682 AN: 251398 AF XY: 0.00532

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0362

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.0128

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00201 AC: 2936 AN: 1461892 Hom.: 46 Cov.: 30 AF XY: 0.00187 AC XY: 1362 AN XY: 727248

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.0343 AC: 1535 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 262 AN: 26136

East Asian (EAS) AF: 0.0184 AC: 729 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000199 AC: 221 AN: 1112012

Other (OTH) AF: 0.00252 AC: 152 AN: 60396

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152274 Hom.: 3 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74452

African (AFR) AF: 0.000987 AC: 41 AN: 41548

American (AMR) AF: 0.0137 AC: 210 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.0139 AC: 72 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68032

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00465

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.4
DANN	Benign	0.82
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs149619575; hg19: chr2-54891760; COSMIC: COSV61690475; COSMIC: COSV61690475;