chr16-69187223-G-T

Variant names:

• chr16-69187223-G-T
• rs1443372786
• NM_006750.4:c.57G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006750.4(SNTB2):​c.57G>T​(p.Trp19Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000772 in 1,295,226 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: SNTB2 NM_006750.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83
• Publications: 0 publications found

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]

UTP4 Gene-Disease associations (from GenCC):

• hereditary North American Indian childhood cirrhosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet
• cirrhosis, familial

  Inheritance: AR Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006750.4. 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
	SNTB2	NM_006750.4	MANE Select	c.57G>T	p.Trp19Cys	missense	Exon 1 of 7	NP_006741.1	Q13425-1
	SNTB2	NR_172088.1		n.60G>T		non_coding_transcript_exon	Exon 1 of 8
	SNTB2	NR_172089.1		n.60G>T		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNTB2	ENST00000336278.9	TSL:1 MANE Select	c.57G>T	p.Trp19Cys	missense	Exon 1 of 7	ENSP00000338191.4	Q13425-1
	SNTB2	ENST00000467311.5	TSL:1	n.57G>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000436443.1	Q13425-2
	SNTB2	ENST00000958019.1		c.57G>T	p.Trp19Cys	missense	Exon 1 of 7	ENSP00000628078.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1295226 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 639388

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27034

American (AMR) AF: 0.00 AC: 0 AN: 22248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20542

East Asian (EAS) AF: 0.00 AC: 0 AN: 30436

South Asian (SAS) AF: 0.00 AC: 0 AN: 66130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3964

European-Non Finnish (NFE) AF: 9.67e-7 AC: 1 AN: 1033976

Other (OTH) AF: 0.00 AC: 0 AN: 52426

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.098	T
Sift4G	Benign	0.098	T
Polyphen		0.061	B
Vest4		0.57
MutPred		0.68		Loss of MoRF binding (P = 0.0069)
MVP		0.63
MPC		2.2
ClinPred		0.88	D
GERP RS		4.6
PromoterAI		0.13	Neutral
Varity_R		0.29
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1443372786; hg19: chr16-69221126;