16-69187395-G-T

Variant names:

• chr16-69187395-G-T
• rs779603981
• NM_006750.4:c.229G>T

Variant summary

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

The NM_006750.4(SNTB2):​c.229G>T​(p.Gly77Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000504 in 1,274,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: SNTB2 NM_006750.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

Genes affected

SNTB2 (HGNC:11169): (syntrophin beta 2) Dystrophin is a large, rod-like cytoskeletal protein found at the inner surface of muscle fibers. Dystrophin is missing in Duchenne Muscular Dystrophy patients and is present in reduced amounts in Becker Muscular Dystrophy patients. The protein encoded by this gene is a peripheral membrane protein found associated with dystrophin and dystrophin-related proteins. This gene is a member of the syntrophin gene family, which contains at least two other structurally-related genes. [provided by RefSeq, Jul 2008]

UTP4 (HGNC:1983): (UTP4 small subunit processome component) This gene encodes a WD40-repeat-containing protein that is localized to the nucleolus. Mutation of this gene causes North American Indian childhood cirrhosis, a severe intrahepatic cholestasis that results in transient neonatal jaundice, and progresses to periportal fibrosis and cirrhosis in childhood and adolescence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

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=0.03595099).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNTB2	NM_006750.4	c.229G>T	p.Gly77Cys	missense_variant	Exon 1 of 7	ENST00000336278.9	NP_006741.1
SNTB2	NR_172088.1	n.232G>T		non_coding_transcript_exon_variant	Exon 1 of 8
SNTB2	NR_172089.1	n.232G>T		non_coding_transcript_exon_variant	Exon 1 of 7
SNTB2	NR_172090.1	n.232G>T		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNTB2	ENST00000336278.9	c.229G>T	p.Gly77Cys	missense_variant	Exon 1 of 7	1	NM_006750.4	ENSP00000338191.4
SNTB2	ENST00000467311.5	n.229G>T		non_coding_transcript_exon_variant	Exon 1 of 6	1		ENSP00000436443.1
UTP4	ENST00000567287.2	n.82+20210G>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.000301 AC: 45 AN: 149290 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000210

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000462

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000878 AC: 3 AN: 3418 Hom.: 0 AF XY: 0.00126 AC XY: 3 AN XY: 2372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000531 AC: 597 AN: 1124900 Hom.: 1 Cov.: 30 AF XY: 0.000567 AC XY: 308 AN XY: 542952

Gnomad4 AFR exome AF: 0.000132

Gnomad4 AMR exome AF: 0.000468

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000353

Gnomad4 FIN exome AF: 0.000129

Gnomad4 NFE exome AF: 0.000592

Gnomad4 OTH exome AF: 0.000313

GnomAD4 genome AF: 0.000301 AC: 45 AN: 149290 Hom.: 0 Cov.: 31 AF XY: 0.000206 AC XY: 15 AN XY: 72808

Gnomad4 AFR AF: 0.000219

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000210

Gnomad4 NFE AF: 0.000462

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000810 Hom.: 0

Bravo AF: 0.000348

ExAC AF: 0.0000850 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229G>T (p.G77C) alteration is located in exon 1 (coding exon 1) of the SNTB2 gene. This alteration results from a G to T substitution at nucleotide position 229, causing the glycine (G) at amino acid position 77 to be replaced by a cysteine (C). 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	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.022
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.023	D
Polyphen		0.0030	B
Vest4		0.19
MVP		0.60
MPC		1.6
ClinPred		0.12	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.54

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

Other links and lift over

dbSNP: rs779603981; hg19: chr16-69221298;