16-69187723-C-A

Variant names:

• chr16-69187723-C-A
• rs760371993
• NM_006750.4:c.557C>A

Variant summary

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

The NM_006750.4(SNTB2):​c.557C>A​(p.Ala186Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000908 in 1,101,914 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A186V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: SNTB2 NM_006750.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33
• 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.557C>A	p.Ala186Glu	missense	Exon 1 of 7	NP_006741.1	Q13425-1
	SNTB2	NR_172088.1		n.560C>A		non_coding_transcript_exon	Exon 1 of 8
	SNTB2	NR_172089.1		n.560C>A		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.557C>A	p.Ala186Glu	missense	Exon 1 of 7	ENSP00000338191.4	Q13425-1
	SNTB2	ENST00000467311.5	TSL:1	n.557C>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000436443.1	Q13425-2
	SNTB2	ENST00000958019.1		c.557C>A	p.Ala186Glu	missense	Exon 1 of 7	ENSP00000628078.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 9.08e-7 AC: 1 AN: 1101914 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 543718

African (AFR) AF: 0.00 AC: 0 AN: 20746

American (AMR) AF: 0.00 AC: 0 AN: 26760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14998

East Asian (EAS) AF: 0.00 AC: 0 AN: 9248

South Asian (SAS) AF: 0.00 AC: 0 AN: 73528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3394

European-Non Finnish (NFE) AF: 0.00000111 AC: 1 AN: 897414

Other (OTH) AF: 0.00 AC: 0 AN: 40004

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.78	P
Vest4		0.56
MutPred		0.68		Gain of disorder (P = 0.0259)
MVP		0.66
MPC		0.63
ClinPred		0.97	D
GERP RS		3.4
PromoterAI		0.091	Neutral
Varity_R		0.89
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760371993; hg19: chr16-69221626;