14-67204578-C-T

Variant names:

• chr14-67204578-C-T
• rs763782646
• NM_001395907.1:c.401C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001395907.1(GARIN2):​c.401C>T​(p.Ala134Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A134G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: GARIN2 NM_001395907.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.541
• Publications: 0 publications found

Genes affected

GARIN2 (HGNC:20101): (golgi associated RAB2 interactor family member 2)

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

GPHN Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05501932).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395907.1. 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
	GARIN2	NM_001395907.1	MANE Select	c.401C>T	p.Ala134Val	missense	Exon 5 of 8	NP_001382836.1	A0A8V8TKJ2
	GARIN2	NM_173526.4		c.401C>T	p.Ala134Val	missense	Exon 5 of 9	NP_775797.2	Q8N9W8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARIN2	ENST00000696955.1	MANE Select	c.401C>T	p.Ala134Val	missense	Exon 5 of 8	ENSP00000512992.1	A0A8V8TKJ2
	GARIN2	ENST00000534174.5	TSL:1	c.401C>T	p.Ala134Val	missense	Exon 5 of 10	ENSP00000432195.1	Q8N9W8-2
	GARIN2	ENST00000612183.4	TSL:2	c.401C>T	p.Ala134Val	missense	Exon 5 of 9	ENSP00000483154.1	Q8N9W8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250170 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461208 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 726786

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111680

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.7
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.055	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.54
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.12	T
Polyphen		0.17	B
Vest4		0.13
MVP		0.030
GERP RS		2.0
PromoterAI		0.00030	Neutral
Varity_R		0.084
gMVP		0.34

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: rs763782646; hg19: chr14-67671295; COSMIC: COSV61295060; COSMIC: COSV61295060;