chr16-69187479-G-T

Variant names:

• chr16-69187479-G-T
• rs749828433
• NM_006750.4:c.313G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006750.4(SNTB2):​c.313G>T​(p.Gly105Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,223,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G105S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: SNTB2 NM_006750.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.668
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12809426).

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.313G>T	p.Gly105Cys	missense	Exon 1 of 7	NP_006741.1	Q13425-1
	SNTB2	NR_172088.1		n.316G>T		non_coding_transcript_exon	Exon 1 of 8
	SNTB2	NR_172089.1		n.316G>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.313G>T	p.Gly105Cys	missense	Exon 1 of 7	ENSP00000338191.4	Q13425-1
	SNTB2	ENST00000467311.5	TSL:1	n.313G>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000436443.1	Q13425-2
	SNTB2	ENST00000958019.1		c.313G>T	p.Gly105Cys	missense	Exon 1 of 7	ENSP00000628078.1

Frequencies

GnomAD3 genomes AF: 0.00000673 AC: 1 AN: 148516 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.30e-7 AC: 1 AN: 1075338 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 508742

⚠️ 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: 22460

American (AMR) AF: 0.00 AC: 0 AN: 8010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13476

East Asian (EAS) AF: 0.00 AC: 0 AN: 25494

South Asian (SAS) AF: 0.00 AC: 0 AN: 21394

European-Finnish (FIN) AF: 0.0000349 AC: 1 AN: 28632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3092

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 910404

Other (OTH) AF: 0.00 AC: 0 AN: 42376

⚠️ 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 AF: 0.00000673 AC: 1 AN: 148516 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 1 AN XY: 72328

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

African (AFR) AF: 0.00 AC: 0 AN: 41018

American (AMR) AF: 0.00 AC: 0 AN: 14966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66618

Other (OTH) AF: 0.00 AC: 0 AN: 2042

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.67
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.021
Sift	Benign	0.051	T
Sift4G	Uncertain	0.052	T
Polyphen		0.085	B
Vest4		0.18
MutPred		0.28		Gain of glycosylation at P103 (P = 0.091)
MVP		0.42
MPC		1.6
ClinPred		0.33	T
GERP RS		1.2
PromoterAI		-0.095	Neutral
Varity_R		0.11
gMVP		0.52

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: rs749828433; hg19: chr16-69221382;