rs1741489

Variant names:

• chr14-64779145-C-G
• rs1741489
• NM_001355436.2:c.4563+12G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-64779145-C-G
• chr14-64779145-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001355436.2(SPTB):​c.4563+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,607,658 control chromosomes in the GnomAD database, including 61,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11229 hom., cov: 31)
  • Exomes 𝑓: 0.25 (50761 hom.)
• Consequence: SPTB NM_001355436.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0850
• Publications: 8 publications found

Genes affected

SPTB (HGNC:11274): (spectrin beta, erythrocytic) This locus encodes a member of the spectrin gene family. Spectrin proteins, along with ankyrin, play a role in cell membrane organization and stability. The protein encoded by this locus functions in stability of erythrocyte membranes, and mutations in this gene have been associated with spherocytosis type 2, hereditary elliptocytosis, and neonatal hemolytic anemia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

SPTB Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-64779145-C-G is Benign according to our data. Variant chr14-64779145-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355436.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	NM_001355436.2	MANE Select	c.4563+12G>C		intron	N/A	NP_001342365.1
	SPTB	NM_001024858.4		c.4563+12G>C		intron	N/A	NP_001020029.1
	SPTB	NM_001355437.2		c.4563+12G>C		intron	N/A	NP_001342366.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.4563+12G>C		intron	N/A	ENSP00000495909.1
	SPTB	ENST00000553938.5	TSL:1	c.558+12G>C		intron	N/A	ENSP00000451324.1
	SPTB	ENST00000389722.7	TSL:2	c.4563+12G>C		intron	N/A	ENSP00000374372.3

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51844 AN: 151772 Hom.: 11202 Cov.: 31

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.323

GnomAD2 exomes AF: 0.267 AC: 66065 AN: 247232 AF XY: 0.270

Gnomad AFR exome AF: 0.616

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.329

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.229

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.252 AC: 366858 AN: 1455770 Hom.: 50761 Cov.: 32 AF XY: 0.255 AC XY: 184511 AN XY: 724224

African (AFR) AF: 0.631 AC: 21023 AN: 33296

American (AMR) AF: 0.145 AC: 6447 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6958 AN: 26044

East Asian (EAS) AF: 0.321 AC: 12691 AN: 39502

South Asian (SAS) AF: 0.366 AC: 31447 AN: 85838

European-Finnish (FIN) AF: 0.220 AC: 11679 AN: 53122

Middle Eastern (MID) AF: 0.292 AC: 1562 AN: 5354

European-Non Finnish (NFE) AF: 0.233 AC: 258071 AN: 1107944

Other (OTH) AF: 0.283 AC: 16980 AN: 60090

GnomAD4 genome AF: 0.342 AC: 51908 AN: 151888 Hom.: 11229 Cov.: 31 AF XY: 0.340 AC XY: 25234 AN XY: 74250

African (AFR) AF: 0.612 AC: 25332 AN: 41364

American (AMR) AF: 0.208 AC: 3184 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3472

East Asian (EAS) AF: 0.337 AC: 1739 AN: 5158

South Asian (SAS) AF: 0.381 AC: 1839 AN: 4824

European-Finnish (FIN) AF: 0.228 AC: 2404 AN: 10536

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15513 AN: 67944

Other (OTH) AF: 0.319 AC: 672 AN: 2108

Alfa AF: 0.181 Hom.: 524

Bravo AF: 0.349

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Elliptocytosis (1)
-	-	1	Hereditary spherocytosis type 2 (1)
-	-	1	not specified (1)
-	-	1	Spherocytosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.65
PhyloP100		-0.085
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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: rs1741489; hg19: chr14-65245863; COSMIC: COSV67630499;